- Email: [email protected]
Recent advances in bone-targeted therapy
Journal Pre-proof Recent advances in bone-targeted therapy
Chen Shi, Tingting Wu, Yu He, Yu Zhang, Dehao Fu PII:
S0163-7258(20)30001-2
DOI:
https://doi.org/10.1016/j.pharmthera.2020.107473
Reference:
JPT 107473
To appear in:
Pharmacology and Therapeutics
Please cite this article as: C. Shi, T. Wu, Y. He, et al., Recent advances in bone-targeted therapy, Pharmacology and Therapeutics(2020), https://doi.org/10.1016/ j.pharmthera.2020.107473
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P&T #23607 Recent advances in bone-targeted therapy Chen Shi a,# , Tingting Wu a,# , Yu He b , Yu Zhang a, Dehao Fu b,* a
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong
University of Science & Technology (HUST), Wuhan, P.R. China Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong
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b
Corresponding author:
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*
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University of Science & Technology (HUST), Wuhan, P.R. China
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Dehao Fu, Department of Orthopaedics, Union Hospital, Tongji Medical College,
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Huazhong University of Science & Technology (HUST), 1277 Jiefang Avenue,
Wuhan 430022, P.R. China. Email: [email protected]
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These authors contributed equally to this work.
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#
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Abstract
The coordination between bone resorption and bone formation plays an essential role in keeping the mass and microstructure integrity of the bone in a steady state. However, this balance can be disturbed in many pathological conditions of the bone. Nowadays, the classical modalities for treating bone-related disorders are being challenged by severe obstacles owing to low tissue
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selectivity and considerable safety concerns. Moreover, as a highly mineralized tissue, the bone
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shows innate rigidity, low permeability, and reduced blood flow, features that further hinder the
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effective treatment of bone diseases. With the development of bone biology and precision
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medicine, one novel concept of bone-targeted therapy appears to be promising, with improved
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therapeutic efficacy and minimized systematic toxicity. Here we focus on the recent advances in
bone-targeted treatment based on the unique biology of bone tissues. We summarize commonly
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used bone targeting moieties, with an emphasis on bisphosphonates, tetracyclines, and biomimetic
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bone-targeting moieties. We also introduce potential bone-targeting strategies aimed at the bone
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matrix and major cell types in the bone. Based on these bone-targeting moieties and strategies, we discussed the potential applications of targeted therapy to treat bone diseases. We expect that this review will put together useful insights to help with the search for therapeutic efficacy in bone-related conditions.
Keywords: Bone targeting, osteoblasts, osteoclasts, bone remodeling, bone formation, bone resorption
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Contents
1. Introduction 2. Bone structure and biology 3. Bone-targeting moieties 4. Bone-targeting strategies
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5. Targeted therapy for bone-related diseases
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6. Conclusion and perspectives
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Conflicts of interest
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Acknowledgements
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References
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Abbreviations
Asp,
aspartic
acid;
ALN,
alendronate;
BMPs,
bone
morphogenetic
proteins;
BPs,
bisphosphonates; BSP, bone sialoprotein; BMD, bone mineral density; CAP, chondrocyte-homing peptide; CBDs, collagen binding domains; CDs, carbon dots; DC, doxycycline; DOX, doxorubicin; ET-1, endothelin-1; Glu, glutamic acid; HA, hydroxyapatite; MMPs, matrix
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metalloproteinases; MSCs, mesenchymal stem cells; OPG, osteoprotegerin; PDB, Paget's disease of bone; PTH, parathyroid hormone; PGE2, prostaglandin E2; PLGA, Poly(lactic-coglycolic
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acid); RANK, receptor activator of NF-κB; SAA, salvianic acid A; SAON, steroid-associated
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osteonecrosis; Sct, Salmon calcitonin; SERMs, selective estrogen receptor modulators; SELEX,
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systematic evolution of ligands by exponential enrichment; TCs, tetracyclines; TKIs, tyrosine
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kinase inhibitors; VEGF, vascular endothelial growth factor; ZA, zoledronic acid.
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1. Introduction
The bone is a specified connective tissue with highly mineralized architecture and structure (Burr, 2019). As an internal support system, the bone provides a structural foundation for the body and sites for muscle attachment for locomotion. Additionally, the bone offers protection to the brain and splanchnic organs, as well as a house for hematopoietic tissues of the bone marrow. The
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bone is also the primary source and depot of inorganic ions, especially phosphate and calcium,
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which can participate actively in mineral homeostasis and energy metabolism in the body
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(Florencio-Silva, et al., 2015). For the healthy development and maintenance of the skeleton, the
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bone undergoes a constant modeling and remodeling process through bone formation by
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osteoblasts and bone resorption by osteoclasts (Low & Kopecek, 2012). Under healthy
physiological conditions, the balance between bone-resorption and rebuilding is well-coordinated,
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which can keep the microstructure integrity and mass of the bone in a steady state. However, this
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equilibrium would be disturbed in many bone diseases (Rodan & Martin, 2000).
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As the most prevalent form of bone metabolic disorders, osteoporosis has a high incidence in women and men over 50, especially postmenopausal women. Osteosarcoma and bone metastasis, other types of imbalances in bone metabolism, could cause significant pain and increase mortality rates in patients. Other diseases, including osteoarthritis, osteomyelitis, and Paget's disease of bone (PDB), could amplify the economic burden and decrease the quality of life for millions of individuals worldwide. With an advanced understanding of bone biology, the treatment of bone diseases has been
improved but still faces significant obstacles in the clinic. Estrogen replacement therapy is usually utilized for osteoporosis in postmenopausal women. However, the treatment remains a source of 5
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considerable concerns after prolonged administration, especially as a potential risk for breast cancer, uterus cancer, and endometritis (Astedt, 1982; Wallach & Gambrell, 1982). Parathyroid hormone (PTH), the most frequently used anabolic, is effective in stimulating bone formation. Unfortunately, the anabolic effect of PTH is only limited to two years, owing to a secondary osteoclastogenic effect that results in bone catabolism over anabolism (Cosman., et al., 2005;
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Neer, et al., 2001). More significantly, patients receiving PTH may also carry an increased risk of
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developing osteosarcoma (Leder, 2017; Lindsay, et al., 1997; Neer, et al., 2001). An RNA
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interference (RNAi)-based therapy aimed at bone disease-associated pathogenic genes offers a
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new genetic medical approach; this therapy is potentially translational therapy for bone-related
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diseases (Novina & Sharp, 2004). However, this modality requires a large therapeutic dose of
systematically administered siRNA, which would increase cost and safety concerns (Itaka, et al.,
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2007). Moreover, the above chemicals or biotherapies are usually administered systematically
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when treating bone-related disorders. On the one hand, the therapeutic agents have a non-specific
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in vivo bio-distribution, causing undesired side effects to non-skeletal tissues. On the other hand, the low concentration of therapeutics in localized bone would maximize therapeutic efficiency (Carbone, et al., 2017). These limitations leave the field with a significant challenge to surmount in the current bone disease treatment strategies. Hence, the development of effective and innovative therapies against bone-related diseases is highly desirable. The most important clinical objective in treating clinical diseases is to realize precise therapeutic efficacy in defined pathological s ites. Specific treatment for bone-related disorders
also inspires abundant interests. Pierce et al (William M. Pierce, 1987) first proposed the concept of ‘bone-targeting’ in 1986, providing new insights into bone diseases. With years of concerted 6
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efforts, targeted therapy has made considerable progress in bone disease treatment (He, et al., 2017; Hirabayashi & Fujisaki, 2003; Sousa & Clezardin, 2018; Zhang, et al., 2018). By endowing bone therapeutic agents with osteotropicity, their pharmacokinetic profile can be altered significantly to a favorable skeletal deposition. This therapeutic regiment in bone tissues would work sustainably and effectively to improve the local therapeutic index (Wang, et al., 2005).
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Besides, the preferential accumulation of therapeutics in the bone can decrease the systematic
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distribution to other tissues, potentially minimizing systemic toxicity and long-term concerns
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remarkably (E. J. Carbone, et al., 2017). Also, the required dose of therapeutic agents in
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bone-targeted therapy for local application is smaller when compared to doses used in traditional
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treatments (Cheng, et al., 2017). Given these unique advantages, bone-targeted treatment could
serve as a promising modality in the therapeutic field of bone diseases.
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In this review, we will focus on the advances in recent findings on bone-targeted therapy
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based on the unique biology of bone tissues. We will strive to introduce the commonly used
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bone-targeting moieties, with emphasis on bisphosphonates (BPs), tetracyclines (TCs), and bone-targeting biologicals. We will also summarize the main bone-targeting strategies aimed at the bone matrix and major cell types, such as osteoblasts, bone lining cells, osteoclasts, and osteocytes in bone tissues. We will then discuss the potential and promising applications of targeted therapy to treat bone diseases, including osteoporosis, osteosarcoma and bone metastasis, osteoarthritis, bone fracture and others based on the bone-targeting moieties and strategies. We hope that this review will provide useful information towards overcoming the current dilemma faced by
bone-related therapies and offer new insights into finding ways to treat bone-related diseases efficiently. 7
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2. Bone structure and biology 2.1. Composition of the bone matrix The composition of the bone varies with its diseases, age, anatomical location, and nutritional status. Generally, an adult bone is composed of an organic matrix (20-40%), inorganic mineral
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(50-70%), water (5-10%), and lipids (1-5%) (Shea & Miller, 2005).
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Organic matrix
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The organic matrix of the bone consists primarily of collagen (approx. 90%), predominantly
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type I collagen, a triple-helical molecule composed of a single alpha-2 chain and two identical
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alpha-1 chains. Collagen is deposited in layers of mature bones, known as lamellae, which endows
the bone tissue with a high density of collagenous filaments. Non-collagenous proteins, such as
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osteonectin, osteopontin, and matrix GLA protein, within the bone matrix, may play a role in the
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matrix mineralization process, while others, like growth factors, bone morphogenetic proteins
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(BMPs), cytokines, and adhesion molecules have important signaling functions (Sommerfeldt & Rubin, 2001). Moreover, proteoglycans, including biglycan, osteoaderin, decorin, and lumican, are also located in the matrix (Florencio-Silva, et al., 2015). Inorganic mineral Bone mineral accounts for 50% and 75% of bone tissue by volume and weight, respectively. The majority of inorganic materials in the bone mineral are calcium and phosphate ions. Significant amounts of sodium, bicarbonate, citrate, potassium, magnesium, zinc, fluorite,
strontium, and barium are also present in the bone (Downey & Siegel, 2006). Notably, calcium and phosphate ions nucleate to form hydroxyapatite (HA) [Ca10 (PO4 )6 (OH)2 ], a plate-like crystal 8
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that is 20-80 nm in length and 2-5 nm in thickness; this crystal can provide strength and rigidity to skeletal load-bearing features. HA also contains many impurities, such as carbonate and magnesium, that cause bone apatite to be crystallized poorly and carbonate substitutes apatite. This imperfection could render apatite more soluble and, thus, enable it to release ions for homeostasis (Shea & Miller, 2005).
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2.2. Bone cell biology
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As a rigid structure, the bone carries a self-repairing ability that can remove and replace
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mineral stores rapidly during metabolic demand and reshape the structure after altering
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mechanical stimuli. Four distinctly different cell types participate in the formation, resorption, and
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maintenance of the bone: osteoblasts, bone lining cells, osteoclasts, and osteocytes (Table 1). Osteoblasts
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Osteoblasts are a group of cells with a cuboidal shape located along the surface of the bone.
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These cells account for 4-6% of total bone cells (Capulli, Paone, & Rucci, 2014). Osteoblasts are
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derived from a mesenchymal stem cell (MSC) lineage and can form a compact layer of cells on the bone surface together with their precursors. Structurally, these cuboidal-shaped cells contain plenty of rough endoplasmic reticula, well-developed Golgi apparatus, and diversified secretory vesicles. These morphological characteristics reflect the protein-synthesizing and secreting activity of these cells (Marks & Popoff, 1988). Functionally, osteoblasts are well known for their prominent bone-forming abilities through the deposition of the organic matrix and participation in subsequent bone mineralization. During this process, osteoblasts first produce collagen,
predominantly type I collagen, non-collagenous proteins (e.g., osteocalcin, bone sialoprotein (BSP) II, and osteopontin), and proteoglycan (e.g., biglycan and decorin) to form an organic 9
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matrix (Florencio-Silva, et al., 2015). Mineralization then takes place in two phases following the organic matrix formation: vesicular phase and fibrillar phase (Burr, 2019; Yadav, et al., 2016). In the vesicular phase, matrix vesicles with variable sizes, ranging from 30 to 200 nm, are released by osteoblasts to the newly formed bone matrix. Osteoblasts then secrete enzymes and alkaline phosphatase (ALP) to release calcium ions from proteoglycan-binding compounds and phosphate
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ions from phosphate-containing compounds, respectively, inside the vesicles, which can further
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form HA crystals (Arana-Chavez, Soares, & Katchburian, 1995). In the fibrillar phase, once the
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calcium and phosphate ions in matrix vesicles supersaturate, their structures are ruptured, and the
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HA crystals diffuse to surrounding matrixes (Boivin, et al., 2008; Silva & Bilezikian, 2015).
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Bone lining cells
Bone lining cells are inactive osteoblasts at the bone surface. These quiescent cells differ
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from active osteoblasts and do not undergo neither bone formation nor resorption.
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Morphologically, bone lining cells are flat-shaped cells with extremely flat nuclei and few
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cytoplasmic organelles that can extend well along the bone surface (Matic, et al., 2016). Depending on the physiological status of the bone, bone lining cells can reacquire secretory abilities, increase in size, and adopt a cuboidal shape (Miller, et al., 1989). When bone resorption does not initiate, these cells prevent direct contact between bone matrixes and osteoclasts and participate in osteoclast differentiation (Hienz, Paliwal, & Ivanovski, 2015). Bone lining cells are also a substantial portion of the temporary anatomical structure noted as the basic multicellular unit during the bone remodeling process (Everts, 2002).
Osteoclasts
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Osteoclasts are polarized, multinucleated giant cells that originate from hematopoietic stem cell lineage. The most important characteristic of osteoclasts is their ability to resorb fully mineralized bones (Detsch & Boccaccini, 2015). Resorption begins with the activation of osteoclasts, which requires osteoclasts to attach to the bone surface (Teitelbaum, 2000). Bone resorption then occurs in a particular invaginated cell specialization zone known as the “ruffled
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border,” the site of proteolytic enzyme and acid release for matrix degradation and mineral
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dissolution (Merolli, et al., 2018). Subsequently, the degraded matrix and mineral byproducts are
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transported to the extracellular environment at the opposite side of the cells from the ruffled
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border. After the degradation process, osteoclasts either become inactive or directly die via cell 3
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apoptosis. Generally, an activated osteoclast can complete 200,000 µm worth of resorption per
day, which is nearly equal to the bone formation rate by 7 to 10 generations of osteoblasts with a
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15 to 20 days lifespan (Sommerfeldt & Rubin, 2001). Reportedly, osteoclasts also possess other
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Osteocytes
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functions, such as the direct regulation of the hematopoietic stem cell niche (Julia F, 2014).
As the most abundant and long-living cells in bone cell populations, osteocytes comprise 90% to 95% of all bone cells and have an extremely long lifespan of up to 25 years (Franz-Odendaal, Hall, & Witten, 2006). Osteocytes are derived from MSCs through the differentiation of osteoblasts. Though the precise mechanisms of how osteoblasts become osteocytes remain elusive, it is believed that an embedding mechanism may explain the transmission process. Compared to neighboring cells, a subpopulation of osteoblasts on bone
surface slow down their matrix production and then become “buried alive” in the mineralized matrix produced by adjacent osteoblasts (Franz-Odendaal, Hall, & Witten, 2006). After 11
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transmission, osteocytes display distinctly different structures and functionalities. Compared to osteoblasts, osteocytes have a smaller size, increased nucleus to cytoplasm ratio, and fewer cell organelles. Osteocytes also show a dendritic morphology with a higher number of filopodia (Sommerfeldt & Rubin, 2001). Though they cannot achieve bone formation directly like osteoblasts, they have several important roles. Typically, osteocytes can permit the diffusion of
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mineral and fluids, helping to maintain bone mineral homeostasis (Shea & Miller, 2005).
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Additionally, osteocytes can detect mechanical pressures and serve as mechanosensors, promoting
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the adaptation of the bone to daily mechanical forces (Rochefort, Pallu, & Benhamou, 2010). This
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Prideaux, Findlay, & Atkins, 2016).
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cell type can also regulate the activities of both osteoblasts and osteoclasts (Mori & Burr, 1993;
The interconnection between bone cells and matrix in bone microenvironment
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It has been suggested that the crosstalk between bone cells should be a coordinate process for
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steady bone formation and resorption. Initially, the detailed mechanism of this crosstalk was not
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well understood for years. It was not until 1997 that a molecular bas is for the intercellular crosstalk was discovered in the form of osteoprotegerin (OPG) and its cognate ligand OPG-L. OPG is secreted by osteoblasts, while the OPG-L is expressed on osteoblasts. Both molecules can bind with the receptor activator of NF-κB (RANK) to activate the downstream signal, a typical transmembranous receptor expressed on osteoclast precursors. The binding of OPG-L (also known as RANK-L) on osteoblasts with RANK induces a signaling and gene expression cascade, promoting the formation of osteoclasts from precursors (Ahmed, 2015; Hofbauer, et al., 2000). In
contrast, OPG competes with RANK to bind with RANK-L, which can inhibit osteoclast formation and subsequent bone resorption effectively. 12
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Recently, semaphorins (Sema) have been revealed as key molecules participating in the cell-cell communication between osteoblasts and osteoclasts (Hayashi, et al., 2012). Among the identified semaphorin families, two types are closely related to cell crosstalk. Semaphorin 3A (Sema3A) produced by osteoblasts inhibits osteoclasts, while Semaphorin 4D (Sema4D) secreted by osteoclasts inhibits osteoblasts (Negishi-Koga & Takayanagi, 2012). Other factors are also
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involved in the bone remodeling process. EphrinB2 (Eph2), a membrane-bound molecule located
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on osteoclasts, can bind with ephrinB4 (Eph4) expressed on osteoblast membranes. Remarkably,
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their bindings transduce bidirectional signals. An Eph2/Eph4 binding facilitates the differentiation
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of osteoclasts, whereas a reversed Eph4/Eph2 signaling decreases osteoclastogenesis (Zhao, et al.,
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2006).
Located within lacunae encompassed by highly mineralized bone matrices, osteocytes harbor
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numerous cytoplasmic processes that function through small channels, expediting their
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interconnection with neighboring osteocytes, bone lining cells, and osteoblasts on the bone
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surface. Osteocytes, like osteoblasts, can secret RANK-L or OPG to promote or inhibit osteoclastogenesis, respectively. Also, upon mechanical stimulus, osteocytes secret secondary factors to modify bone physiology. Moreover, nitric oxide (NO), prostaglandin E2 (PGE2), and insulin-like growth factor-1 (IGF-1) can stimulate osteoblast activity, while sclerostin and the dickkopf WNT signaling pathway inhibitor (DKK-1) play a converse role. The extracellular matrix is closely associated with the bone cells and plays an essential role in bone homeostasis. The collagenous matrix generated by osteoblast-progenitors regulate growth
factors (e.g. BMPs), facilitating osteoblast differentiation and matrix maturation (Yang, et al., 2003). Osteoblasts/osteocytes produce matrix metalloproteinases (MMPs) which promote the 13
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remodeling of matrix and development of the lacunocanalicular system. Osteocytes also secrete dentin matrix protein 1 (DMP1) and matrix extracellular phosphoglycoprotein (MEPE) to regulate calcium and phosphate metabolism in matrix (Alford, Kozloff, & Hankenson, 2015). Furthermore, various matrix proteins provide RGD binding sites to bind with integrins on osteoclast, enabling the formation of ruffled border and sealing off of resorptive spaces, where cathepsin K and
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hydrogen ions are then surrounded to degrade type I collagen and demineralize inorganic
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components, respectively (Lakkakorpi, et al., 1991). Along with bone resorbing process,
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osteoclasts regulate extracellular calcium concentration, and in turn, the extracellular and
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intracellular calcium level influence the osteoclast activity (Li, Kong, & Qi, 2006). Apart from
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bone cells, PTH act as a major regulator of the levels of calcium and phosphate in the bone matrix (Wein & Kronenberg, 2018).
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As multipotent stromal cells, MSCs are capable of osteogenic differentiation (Grayson, et al.,
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2015). The bone marrow microenvironment created during bone remodeling directs the fate of
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MSCs. IGF-1 released from the bone matrix can stimulate the differentiation of MSCs to osteoblasts by activating mammalian target of rapamycin (Xian, et al., 2012). Transforming growth factor β (TGF-β), which is released and activated by osteoclasts, can recruit MSCs specifically to local site of repair for new bone formation. The expression of Sema4D on osteoclasts, on the other hand, inhibits MSC differentiation (Crane & Cao, 2014) (Figure 1).
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Figure 1. The interconnection between bone cells and matrix in bone microenvironment.
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Osteoblasts express RANK-L or secret OPG to bind with RANK on osteoclast precursors, which
facilitate or inhibit osteoclast formation, respectively. Sema3A produced by osteoblasts inhibits
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osteoclasts, while Sema4D secreted by osteoclasts inhibits osteoblasts. Eph2, a membrane-bound
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molecule present on osteoclasts, binds with Eph4 expressed on osteoblasts. Eph2/Eph4 binding
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facilitates the differentiation of osteoclasts, when a reversed Eph4/Eph2 signaling decreases osteoclastogenesis. Osteocytes secret RANK-L or OPG to promote or inhibit osteoclastogenesis, respectively. Osteocytes also produce NO, PGE2 and IGF-1 to stimulate osteoblast activity, while release sclerostin and
DKK-1
to
inhibit
osteoblast
activity.
For
matrix
regulation,
osteoblasts/osteocytes produce MMPs to promote the remodeling of matrix and development of the lacunocanalicular system. Cathepsin K and hydrogen ions in ruffled border degrade type I collagen and demineralize inorganic components, respectively. IGF-1 released from the bone
matrix stimulates MSCs differentiation to osteoblasts. TGF-β released by osteoclasts recruits
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MSCs to local site of repair for bone formation while Sema4D inhibit MSC differentiation. More in-depth discussions please refer to the text.
3. Bone-targeting moieties Because of its unique structure and composition, the bone also provides opportunities for
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varieties of agents called bone mineral seekers to selectively target skeletal tissues. Years of
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extensive investigations have demonstrated that different types of moieties, including many small
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molecules (< 1000 Da), as well as large macromolecular proteins, show high bone specificity.
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Typical bone-targeting moieties are classified in Table 2 and will be discussed in detail in the
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following paragraphs.
3.1. Bisphosphonates
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BPs are a class of analogs of naturally occurring pyrophosphates. Fleisch and colleagues first
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reported the biological function of BPs in the 1960s (Mühlbauer, 1968). Since then, BPs have
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been investigated extensively for biomedical applications. These analogs possess a similar ability to regulate bone mineralization as pyrophosphates but are much more chemically stable than pyrophosphates. Structurally, the two phosphonate groups (PO(O−)2) share a common oxygen molecule (P–O–P) in pyrophosphates, but the oxygen molecule in BPs is replaced by a carbon atom (P–C–P). The substitution of the P-C-P backbone in BPs does not affect its affinity for bone minerals but makes it more resistant to most chemical reagents and enzymatic degradation, resulting in an extended residence for BPs in skeletal tissues for up to years (Brown, et al., 2014).
The affinity of BPs for the bone is greatly affected by the molecular structure of BPs. Mechanistically, the P–C–P backbone presents two phosphonate groups to chelate with divalent 16
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interaction with Ca to generate a tridentate binding to HA (Lawson, et al., 2010).
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Based on the presence or absence of nitrogen side groups at the R2 position, BPs can be
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categorized into two groups: nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs
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(non-N-BPs). It has been suggested that the N-BPs possess a higher binding affinity for the bone
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than non-N-BPs (Nancollas, et al., 2006). This difference in affinity could be attributed to the
direct hydrogen bonding action between nitrogen functional groups and the hydroxyl on a HA
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surface. Moreover, N-BPs can significantly inhibit the synthesis of farnesyl pyrophosphate that is
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necessary for osteoclast functioning (Drake, Clarke, & Khosla, 2008). The in vivo bone
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homeostasis will then be shifted toward bone formation due to the reduced osteoclast activity, which does not affect osteoblast bone formation. Non-N-BPs can be metabolized to toxic methylene-containing adenos ine triphosphate (ATP) analog in bone cells, including osteoclasts, inducing substantial cell apoptosis (Reyes, et al., 2016). Besides, the chemical groups positioned at the R1 and R2 chains can be conjugated with nonspecific bone therapeutic agents to obtain osteotropicity (Rotman, et al., 2018). The use of BPs as bone-targeting moieties still faces several potential complications. Because
BPs can inhibit bone resorption, atypical femur fractures (AFF) could be induced by long-term low bone turnover (Dell, et al., 2012). Compared with AFF, osteonecrosis of the jaw (ONJ) occurs 17
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at a much lower level. However, the occurrence rate of ONJ increases when BPs are used under an oncological condition (Khan, et al., 2015). BPs can also cause extra-skeletal adverse effects, including gastrointestinal effects, cancer of the esophagus, and atrial fibrillation (Reyes, et al., 2016). The gastrointestinal side effects could be related to the poor gastrointestinal absorption of oral BP, which prolongs the exposure of gastric and intestinal mucosa to a large amount of BP
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(Pazianas, et al., 2010). In the meantime, taking pills could induce persistent injury of the mucosa,
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which could lead, potentially, to dysplasia of the esophageal cells and increase the risk of cancer
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of the esophagus (Green, et al., 2010). Atrial fibrillation could result from the increased blood
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calcium level, together with the possible inflammation of arterial wall caused by BP (Abrahamsen,
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Eiken, & Brixen, 2009).
The adverse effects of BPs are correlated with the given dosage. At high doses, BPs could
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inhibit bone mineralization and induce osteomalacia. Patients who have never received BP therapy
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and are given a high dose of BP, may experience a typical acute-phase response with fevers up to
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39°C for 1 to 3 days and transient haematological changes. Besides, the fast intravenous injection of BPs at doses of more than 200 to 300 mg could induce severe renal failure (Adami & Zamberlan, 1996).
3.2. Tetracyclines TCs and their analogs are a family of compounds that display a basic chemical structure comprising a tetracyclic naphthacene carboxamide ring system surrounded by various functional groups and substituents. It is well-known that TCs can bind to bone apatite. This special attraction
to skeletal tissues is mainly attributed to the good metal-complexing abilities of TCs, which can chelate with Ca2+ in the HA of bone matrix (Albert & Rees, 1956). Van der Waals interactions and 18
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hydrogen bonding between TCs and HA are also likely to induce surface complexation to bone apatite, contributing to an additional association between TCs and bones (Wang, Hu, & Zhang, 2010). TCs can equally be conjugated with estrone to develop a bone-targeted estrogen (XW-630). Compared to free estrone, TC-estrone seemed to be more efficient in improving trabecular bone connectivity (Lu, Qiu, & Zheng, 1998). Apart from targeting the skeleton, TCs can as well inhibit
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collagenase with a potent anti-collagenolytic effect, that would reduce bone resorption.
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Furthermore, TCs can increase the expression of procollagen mRNA, elevating the number of
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activated osteoblasts (Reichert, et al., 2012). Interestingly, TCs have fluorescent properties and can
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label the surface of a growing bone formation area, which can be used for imaging and
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quantifying new bone formation (Nakamura, et al., 2000).
Doxycycline (DC), a TC analogue, is also osteotropic with a high affinity for mineralized
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bone. Moreover, DC shows potent benefits for connective tissue remodeling and healing. The
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microenvironment of chronic wounds is pro-inflammatory containing a high level of MMP. DC
et al., 2017).
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displays anti-inflammatory and MMP inhib itory effect , thus promoting normal tissue repair (Gomes,
There are several limitations to using TCs. The inherent biological activity involving heartburn, rash, dizziness, hypoglycemia, and nausea is a considerable concern in the practical use of TCs (Valentín, et al., 2009). Moreover, the chelation of TCs to skeletal tissues is permanent, which leads to undesired side effects, especially for teeth discoloration during dental development in children, and this permanent discoloration from yellow or gray to brown depends on the dose of
TCs (Sánchez, Rogers III, & Sheridan, 2004). Additionally, a high dose of TC may induce enamel hypoplasia during calcification (Bevelander, Rolle, & Cohlan, 1961). Despite high osteotropicity, 19
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TCs show decreased affinity for pathologic skeletal sites with low bone turnover, making TCs suboptimal candidates for bone-related diseases, such as osteomyelitis (J. Hatzenbuehler, 2011). Besides, TCs are quite chemically unstable, which further hinders their clinical application. 3.3. Biomimetic bone-targeting moieties Bone-targeting peptides Recently, utilizing the repetitive acidic amino acids of natural bone proteins to interact with
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Ca2+ in mineralized tissues has emerged as a fundamental bone-targeting concept. Among these
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amino acids, acid oligopeptides, composed of repeating aspartic acid (Asp) or glutamic acid (Glu)
e-
sequences, natively occurring in osteopontin and osteocalcin, show a great affinity for HA
Pr
(Rotman, et al., 2018). Though the exact mechanism is still under debate, the structure of acid
oligopeptides has been demonstrated to correlate to the exclusive interaction between
al
oligopeptides and mineralized tissues. Acid oligopeptides with 4 to 10 Asp or Glu units (Asp4-10,
rn
Glu4-10) are reportedly considered as more biocompatible options for bone-targeting purposes
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(Junko, 2009). The optical isomeric form (L or D) of peptides affects in vivo biocompatibility to some extent. Compared with L-peptides, D-peptides are not readily recognized by the immune system and, thus, promote in vivo biocompatibility (Low & Kopecek, 2012). Oligopeptides’ binding affinity for the bone varies depending on the number of amino acids they contain, the binding rates of small peptides with HA are enhanced with increasing chain lengths of Asp and Glu. However, the binding affinity comes to a steady level when the chain is up to hexapeptides. As a result, acid oligopeptides with over six amino acids in length are the ideal candidates for
binding efficiency requirements. Meanwhile, there is evidence that the chirality of Asp and Glu (L or D) has no impact on mineral chelating properties (Sekido, et al., 2001). 20
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Another oligopeptide, with six repeating sequences of Asp, serine, and serine ((AspSerSer)6), also shows a good skeletal affinity for the bone and has been widely used as a bone-targeting moiety. While Asp8 selectively binds to the bone resorption surface, (AspSerSer)6 displays selective binding to the bone formation surface, as it favorably chelates with osteoblast-mediated mineralizing nodules and amorphous calcium phosphate (Yarbrough, et al., 2010).
f
Apart from oligopeptides, other peptide sequences present osteotropicity. A peptide
oo
consisting of twelve amino acids, VTKHLNQISQSY (VT K), has been confirmed to have a high
pr
affinity for HA and skeleton-like materials. The phosphorylation of serine and the hydroxyl side
e-
group of tyrosine in the VTK peptide sequence are the major interacting domains involved in HA
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binding (William N, 2010).
Bone-targeting proteins
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The most abundant protein in the organic matrix is type I collagen, making it a highly
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potential targeting site in bone tissues. Collagen binding domains (CBDs), largely present in the
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collagenolytic proteases of microorganisms, can bind specifically with collagen (Watanabe, 2004). The cDNA of CBDs can be fused easily into the C-terminus or N- terminus of proteins of interest using standard molecular biology techniques. The fusion-protein, with an unimpaired protein structure and bioactivity, can then be obtained by expressing the recombinant protein. The expected proteins, such as PTH and stromal-derived factor-1-alpha (SDF-1α), can acquire the specific binding ability to collagen in the bone (Sun, et al., 2016; Tulasi, 2011). In addition to collagen, several other matrix proteins, including osteocalcin, sialoprotein, and
osteopontin, account for the minor components of the bone matrix. Interestingly, all of these proteins have been demonstrated to have a good affinity for Ca2+ and the mineral surface of the 21
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bone (Ryuichi Fujisawa, 2012). Osteocalcin, a γ-carboxyglutamic acid-containing protein, is the most abundant non-collagenous protein in the bone. It can bind strongly to HA, instead of amorphous calcium phosphate, preventing crystallization. BSP is an acidic glycol-phosphoprotein in the bone that contains RGD (Arg-Gly-Asp) cell-attachment sequences near the C-terminal end; these sequences can be recognized by the presence of integrin αvβ3 and mediate selective
f
attachments to osteoblasts and fibroblasts (Oldberg, Franzen, & Heinegard, 1988). This protein
oo
also has polyglutamic acid sequences that are responsible for initiating the nucleation of the HA
pr
crystal (Hunter & Goldberg, 1993). Moreover, BSP shows a unique affinity for collagen, which
e-
further increases the potency for HA nucleation (Baht, Hunter, & Goldberg, 2008). Another
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multifunctional protein, osteopontin, also contains RGD adhesive sequences, as well as Asp-rich
calcium-binding domains, which can bind to the surface of HA effectively. In contrast to BSP’s
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Bone-targeting cells
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nucleation, osteopontin is likely to inhibit the formation and growth of the crystal (Boskey, 1995).
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With pluripotent nature, MSCs can be trafficked to injured tissues, also termed endogenous stem cell homing, and participate in subsequent tissue regeneration (Lin, et al., 2017). In bone tissue, MSCs can be recruited to fractured sites via (SDF)1/CXC chemokine receptor (CXCR) 4 signaling axis and improve healing by increasing the bone formation and bone content of the callus (Kitaori, et al., 2009). As described above, TGF-β released by osteoclasts can facilitate MSC recruitment in bone resorptive sites further. Besides, many integrins, including integrin α1, α2, α3, α4, α5, α6, α11 and β1 are expressed in MSCs (Guan, et al., 2012). Among them, the
overexpression of integrin α4 can promote MSC homing to bone (Mukherjee, et al., 2008).
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Although using biomimetic moieties for bone-targeting presents fewer adverse effects in vivo, their limitations should also be noted. The poor stability of enzymatic cleaving and low oral bioavailability constitute the therapeutic concerns of these moieties in their practical utilization. The manufacturing process is similarly quite complicated, labor-intensive, and requires professional laboratory techniques, resulting in relatively high costs. Moreover, special conditions
f
for transport and storage are required (Aoki, et al., 2012; Sun, 2013).
oo
3.4. Other moieties
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In addition to the molecules mentioned above, a few other moieties can also be used to target
e-
the bone. The phosphonate groups in BPs are known to play an essential role in their interaction
properties.
Pr
with bone minerals. So, other phosphonate-containing compounds may likewise show similar
Tetraazacyclotetradecane-1,4,8,11-tetramethylene
phosphonic
acid
and
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ethylenediamine tetra(methylene phosphonic acid), both containing four phosphonate groups, can
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chelate to Ca2+ on skeletal tissues (Lange, et al., 2016). Different from BPs, these compounds
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display a negligible physiological effect on bone metabolism (Rotman, et al., 2018). Recently, thanks to the systematic evolution of ligands by exponential enrichment (SELEX), aptamers consisting of short DNA/RNA oligonucleotides can be screened as targeting molecules with strong specificity and affinity. The SELEX method comprises three procedures: selection, partitioning, and amplification. Before selection, a library of oligonucleotides containing 1015 different unique sequences is first synthesized, then incubated with targeted-molecules for selection. After incubation, the unbound sequences are removed using different methods; then the
bound sequences are amplified by PCR and utilized for a new round of selection. Lastly, the specific cell-targeted aptamer candidates are obtained after several cycles (Zhuo, et al., 2017). In 23
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this way, the CH6 aptamer with the inherent merits of high specificity and efficiency that can directly target osteoblasts is selected (Liang, et al., 2015). Radionuclides, such as Strontium and Lanthanides, due to their similar physical and chemical properties to those of calcium, can preferentially be deposited in bone tissues and participate in the metabolic process of bone minerals (Cawthray, et al., 2015).
oo
f
4. Bone-targeting strategies
Targeted therapy has been investigated extens ively for more than thirty years for use in the
pr
treatment of bone-related diseases. The advantages of the unique characteristics of targeted
e-
therapy show that it can improve drug utilization for increased therapeutic outcomes, as well as
Pr
reduce systemic toxicity-related side effects. Generally, bone-targeting strategies can be classified
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4.1. Bone matrix-targeting
al
into two types: bone matrix-targeting and bone cell-targeting strategies.
Thirty-five percent of the dry weight of the bone is organic collagen, and the rest is mainly
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2+
composed of inorganic HA, which contains 99% of the total Ca
in the body. Given their unique
characteristics, both collagen and HA can serve as potential targets of compounds or molecules deposited in bone tissues.
Fusing therapeutic proteins with CBDs is a strategy that is used frequently to target organic collagen in the bone. PTH, an essential protein in regulating bone remodeling, can activate osteoblasts directly. The protein’s functions are mainly mediated by the PTH receptor (PTH1R) that is expressed on osteocytes and osteoblasts (Silva & Bilezikian, 2015). Generally, CBDs consist of amino acids 861–981 of the ColH collagenase of Clostridium histolyticum (Matsushita, 24
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et al., 1998). The fusion proteins of PTH can be synthesized by conjugating the carboxy-terminus of PTH directly with the amino-terminal of CBD (CBD-TH) or with CBD via an adjacent ColH domain known as a polycystic kidney disease domain (PKD, CBD-PKD-PTH). Both hybrid proteins can preferentially bind to type I collagen and increase cyclic Adenos ine monophosphate (cAMP) accumulation in PTH/PTHrP receptor transfected cells, resulting in an anabolic effect.
f
However, in practical use, PTH-CBD showed a 15% increase in bone mineral density (BMD),
oo
while PTH-PKD-CBD induced a modest increase (5%), with the PKD domain potentially
pr
reducing the availability of PTH to the PTH/PTHrP receptor. The results suggested that the direct
e-
link between PTH and CBD is more suitable for the treatment of bone diseases (Tulasi, 2011).
+
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Besides PTH, CBD can also fuse with SDF-1α to selectively bind with collagen, with the resulting +
proteins potentially promoting CD34 and c-kit endogenous stem cells to home in the injured
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region for bone regeneration (Shi, et al., 2016).
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Many compounds and molecules show a specific affinity for HA, demonstrating an excellent
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potential to target bone minerals. Thanks to the development of the chemical conjugating technique, therapeutic agents can be grafted easily with bone-targeting moieties by a linker element to acquire bone affinity. As analogs of natural pyrophosphates, BPs have a strong affinity for calcified tissues and can bind effectively to HA on the bone surface. PGE2 can stimulate bone formation after in vivo systematic administration (Chyun & Raisz, 1984); it can be coupled chemically to BPs via the C-1 carboxyl group or 15-hydroxyl group of PGE2. Besides, more than one equivalent of PGE2 utilizing a polysubstituted BP has been obtained by incorporating two moles of PGE2 per mole of a BP, with the tethered PEG2-BP found to have a good affinity for the bone and to liberate PGE2 at an acceptable rate to stimulate bone growth (Gil, et al., 1999). 25
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However, the PGE2-BP conjugate has not develop a good medication for clinic, as it showed comparable bone formation effect to the parent PGE2 and limited accumulation in localized bone resorptive areas (Ossipov, 2015). Similarly, chemotherapeutic prodrugs have been prepared by conjugating drug molecules (camptothecin) to BPs through an ester-labile linkage to drugs, with a hydroxy group or carbonate-labile linkage binding of the amine functional group of drugs. The
f
prodrugs have shown a satisfactory binding ability to HA on the bone surface and can easily be
oo
activated hydrolytically in physiological conditions (Erez, et al., 2008).
pr
Apart from BPs, therapeutics can also be linked with other bone targeting moieties. TCs
e-
show a relatively complex chemical structure and poor stability during chemical conjugation. It is
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possible to separate the HA binding domain from TC by structure-activity relationship study. The tricarbonylmethane group in ring A is sufficient for HA binding (Myers, Tochon-Danguy, &
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Baud, 1983). Estradiol can be conjugated with this functional domain to enhance affinity for HA.
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This bone-targeting system improves the in vivo safety profile of estradiol after administration
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(Neale, et al., 2009). Estradiol can likewise be conjugated with aspartic acid oligopeptide. An estradiol prodrug has been synthesized by linking estradiol at position 3 to L-Asp-hexapeptide via succinate and was used to enhance the expression of the mRNAs of type I collagen α, osteopontin, and BSP, while only increasing BMD with negligible influence on the weights of the uterus and liver (Yokogawa, et al., 2001).
With high drug loading efficacy and small particle size, nanoscale devices are promising transporters of therapeutics to diseased portions of the bone and promote sustained drug release to targeted sites (Liu, et al., 2019). Using variable physicochemical properties, nanoparticles can be functionalized eas ily with bone-targeting ligands to improve the bone affinity of packaged 26
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therapeutics. Poly(lactic-co-glycolic acid) (PLGA) is one of the most commonly used polymers with excellent in vivo biocompatibility and biodegradation and has been approved by the Food And Drug Administration (FDA) for biomedical applications; it is currently used for surgical sutures in the clinic (Lu, et al., 2009). Asp-linked PLGA nanoparticles can be fabricated by conjugating aspartic acid with PLGA nanoparticles directly. These osteotropic nanoparticles show
f
significant HA binding capability. A single Asp residue can serve as a targeting moiety for
oo
skeletal tissues (Erica J Carbone, et al., 2017). Another way to prepare Asp-functionalized PLGA
pr
nanoparticles is to synthesize Asp-PEG-PLGA copolymers first and then assemble the copolymers
e-
into nanoparticles. The use of these nanoparticles in previous in vivo bone affinity assay indicated
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that Asp-PEG-PLGA nanoparticles had higher bone-targeting efficacy than nanoparticles that lack Asp (Fu, et al., 2014). By tagging fluorescein isothiocyanate (FITC) with an Asp peptide,
Besides, PLGA can be grafted to TC via an esterification reaction to form a TC-PLGA
rn
2014).
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FITC-labeled Asp-PLGA nanoparticles can be prepared further for in vivo imaging (Jiang, et al.,
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copolymer, and the nanoparticles are then fabricated by a solvent emulsification method and display bone-targeting ability, improved curative effects, and reduced adverse effects to other organs (H. Wang, et al., 2015).
Recently, carbon dots (CDs) have attracted much attention for their convenient synthesis, colorful photoluminescence, and good biocompatibility, which have been used extensively for bioimaging, sensing, optoelectronics, catalysis, and energy conversion (J. Zhang & Yu, 2016). Fluorescent CDs for bone imaging can be fabricated using alendronate (ALN) without a nitrogen-doping precursor via a facile hydrothermal method. These ALN-based CDs have a strong
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binding affinity for bone structures and extended skeletal fluorescence-retaining ability post-injection (Lee, et al., 2019).
4.2. Bone cell-targeting Because therapeutic agents are unable to differentiate between concrete cells in bone tissues, therapeutics will act on reachable cells with non-selectivity. Strategies that target specific cell
oo
f
types realize higher therapeutic efficiency and lower side effects, demonstrating great potential both in basic research and clinical application.
pr
Targeting osteoblasts
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Osteoblasts possess a prominent bone-forming ability and play an essential role in bone
Pr
homeostasis. Osteoblast-specific aptamers can be screened to bind osteoblasts specifically using
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cell-SELEX. In a practical situation, a CH6 aptamer was selected after screening and post-inserted
rn
into the surface of osteogenic pleckstrin homology domain-containing family O member 1
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(Plekho1) siRNA-encapsulated lipid nanoparticles. The aptamer-functionalized nanoparticles promoted the selective uptake of Plekho1 s iRNA by osteoblasts and osteoblast-specific Plekho1 gene silencing, resulting in enhanced bone formation, improved bone microstructure, and ultimately stimulated bone recovery (Liang, et al., 2015).
Polypeptides have been used widely for targeted delivery owing to their simple spatial structure, small molecular weight, high specificity, strong penetrability, and low immunogenicity. As mentioned above, (AspSerSer)6 has a good affinity for the skeleton and can bind selectively to bone formation surfaces. (AspSerSer)6-attached cationic liposomes can be developed and used to deliver Plekho1 siRNAs to bone-formation surfaces with precision (Zhang, et al., 2012). Besides, 28
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(AspSerSer)6-functionalized nanodevices can be used for selectively transporting Sema3A plasmids to osteoblasts (Yang, et al., 2018).
Phage display is a powerful selection technique for high-throughput screening of peptide or protein interactions. Using a phage or plasmid as the vector, exogenous peptide or protein gene could be fused with a bacteriophage coat protein and expressed on the surface of virion (Wu, et
f
al., 2016). Making use of this tool, Sun et al. ( Sun, et al., 2016) selected a peptide sequence
oo
(Ser-Asp-Ser-Ser-Asp, SDSSD) that showed a binding affinity for osteoblast-specific factor 2 and,
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thus, targeted osteoblasts in a ligand-receptor specific manner. The SDSSD peptide was then
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osteoblast bone formation activity.
e-
modified on PU nanomicelles to deliver nucleic acids to osteoblasts accurately, promoting
Targeting osteoclasts
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Osteoclasts have an excellent capability of resorbing the mineralized bones to maintain an in
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vivo stable state of the bone. Many factors participate in this process, making them attractive
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targets in osteoclasts. Integrin αvβ3, an adhesion receptor expressed on the surface of osteoclasts, can promote the adhesion of osteoclasts to the bone matrix for subsequent bone resorption activity. Recently, owing to the development of the Protein Chip technology, the inhibition of protein-protein interactions (PPIs) has been considered an emerging approach in disease treatment. IPS-02001, a small molecule inhibiting integrin αVβ3-osteopontin PPI, was screened a few years back using an in silico docking method-integrated ProteoChip technology; and it inhibited the maturation and resorptive activity of osteoclasts by blocking αVβ3 integrin signaling, which reduced ovariectomy-induced bone loss (Park, et al., 2016). Alongside integrin, the microRNAs
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(miRNAs) in osteoclasts also play a critical role in regulating bone homeostasis. It has been demonstrated that elevated miR-214-3p in osteoclasts is closely associated with increased serum exosomal miR-214-3p and reduced bone formation in elderly fractured female and ovariectomized mice. Osteoclast-targeting platforms containing antagomiR-214-3p can be developed by conjugating a D-Asp8 peptide with a cationic liposome. This system inhibited the expression of
f
miR-214-3p, which in turn promoted bone formation in ovariectomized aging mice (Li, et al.,
oo
2016).
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Targeting osteocytes
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As the most abundant cells in the bone, osteocytes are attractive target sites for their
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important function in bone metabolism. Osteocytes also play a significant role in the crosstalk of osteoclasts and cancer cells. This class of bone cells can manipulate the activity of early cancer
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bone metastasis and subsequent osteoclastogenesis by expressing RANKL, OPG, and sclerostin,
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thereby providing a favorable bone milieu for the settlement of cancer cells (Cui, Evans, & Jiang,
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2016; Zhou, et al., 2015). Therefore, inhibiting osteocyte-mediated osteolysis would suppress the ingrowth and invasiveness of metastatic cancer.
Zoledronic acid (ZA), a third-generation BP, has a high affinity for bone tissues. More importantly, this BP can focus on sites of osteocytes and cancer cells during the early stage of bone metastasis. Additionally, ZA shows a synergistic effect in alleviating metastatic bone destruction alongside traditional Chinese medicine, plumbagin (PL) (Qiao, et al., 2016). A version of an upconversion nanoparticle that contains ZA and PL has also been fabricated, and it specifically targets osteocytes. This system inhibits the phosphorylation of osteocytic protein
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kinase-a, cAMP-response element-binding protein, extracellular regulated protein kinase, and c-Jun N-terminal kinase, in that way decreasing the expression of osteoclastogenic RANKL and sclerostin (Qiao, et al., 2017).
Targeting stem cells
With unlimited self-renewal and excellent differentiating ability into multiple cell types, stem
oo
f
cells have been applied widely in regeneration engineering. Notably, in the aspect of bone injury, MSCs can differentiate into chondrocytes and osteoblasts, contributing to the repair process
pr
(Grayson, et al., 2015). The unique functions of stem cells make them potential targets in the
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bone. Particularly, various surface molecules on stem cells have been identified using large-scale
Pr
analyses, which has paved a way to develop specific affinity reagents for these molecules. Integrin α1, α2, α3, α4, α5, α6, α11, and β1 are expressed on the surfaces of MSCs. Among them, the
al
overexpression of integrin α4 can promote MSCs’ homing to the bone (Mukherjee, et al., 2008).
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Guan et al. (Guan, et al., 2012) synthesized a specific peptidomimetic ligand (LLP2A) against
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integrin α4β1 that had a high affinity for MSCs. By further combining LLP2A with ALN, the resulting compound can facilitate the in vitro migration and osteogenic differentiation of MSCs, as well as in vivo trabecular bone formation. Recently, a DNA aptamer, named Apt19S, was successfully developed using SELEX to target pluripotent stem cells specifically (Hou, et al., 2015). The aptamer was further immobilized on a bilayer scaffold for explic itly recognition and binding with MSCs. After implanting Apt19S into a defective osteochondral area, the aptamer-functionalized scaffold can facilitate the recruitment and binding with MSCs, promoting both the regeneration of defective cartilage and subchondral bone. Moreover, in vivo tests on rats
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have indicated that this kind of scaffold displays excellent performance in the restoration of the osteochondral knee joint (Hu, et al., 2017).
5. Targeted therapy for bone-related diseases
Generally, the coordination between bone-absorbing osteoclasts and bone-forming osteoblasts keeps the bone in a steady state. This equilibrium is disturbed under many pathological
oo
f
conditions of the bone, including osteoporosis, osteosarcoma and bone metastasis, osteoarthritis, bone fracture, and other skeletal disorders. With the development of precision medicine, targeted
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therapy aimed at preselected sites has raised considerable interest in research and achieved much
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rn
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progress in bone-related diseases (Figure 2 and Table 3).
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Figure 2. The schematic illustration of targeted therapy for bone-related diseases.
5.1. Osteoporosis
Osteoporosis is a common skeletal disease characterized by remarkably reduced bone mass and strength, as well as impaired skeletal microarchitecture that, in turn, increases the propensity for fragility fractures. As an emerging socioeconomic and medical threat, osteoporosis has a
oo
f
higher prevalence in the aging population, particularly postmenopausal women. A fracture
pr
caused-osteoporosis occurs mainly in the spine, hip, and wrist, which would result in the loss of
e-
mobility and autonomy. The risk of fracture in the lifetime of patients is as high as 40% (Rachner, Khosla, & Hofbauer, 2011). As a consequence, there is an urgent need for the effective prevention
Pr
and therapy of osteoporosis. Generally, the therapeutic strategies for osteoporosis can be classified
al
into two categories: the suppression of bone loss and enhancement of bone strength by inhibiting
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the antiresorptive activity of osteoclasts and the acceleration of bone formation and reverse of
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bone deterioration by stimulating osteoblasts.
Salmon calcitonin (sCT), an antiresorptive protein, can produce its antiresorptive effect by acting with calcitonin receptors (CTRs) expressed on osteoclasts (Chambers & Magnus, 1982).
However, sCT has low bone selectivity, given that CTRs are also expressed extensively in many non-skeletal tissues. To overcome this issue, sCT is, therefore, conjugated to thiolated-BP via an SMCC-chemistry to improve site-specificity to the bone. Consequently, the conjugate, with the restored bioactivity of sCT, shows enhanced specificity to mineralized tissues. Regrettably, a conclusive in vivo therapeutic efficacy is missing, meaning that further confirmation is required (Bhandari, et al., 2010). 33
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With satisfactory bio-distribution and tissue-specific properties, nanosystems have been broadly
used
for
targeted
therapy.
Hengst
et
al
(Hengst,
et
al.,
2007)
used
cholesteryl-trioxyethylene-bisphosphonic acid as a targeting moiety and developed the bone-targeted liposomes to treat bone-related diseases, such as osteoporosis, with prolonged exposure to therapeutics and minimized systematic side effects. Ryu et al. (Ryu, et al., 2016)
f
designed a category of ALN conjugated nanodiamonds (ALN-NDs) for potential osteoporosis
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treatment. ALN-NDs can accumulate effectively in the bone after intravenous injection and be
pr
employed potentially for the efficient treatment of osteoporosis thanks to the presence of ALN.
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Estrogen plays a key role in regulating bone metabolism in both females and males (Khosla,
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Amin, & Orwoll, 2008). Supposedly, estrogen therapy can prevent and treat osteoporosis effectively (Khos la & Hofbauer, 2017). However, low selectivity by the skeleton has restricted the
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significant application of estrogen. One classical means to acquire accurate site-specificity to the
rn
bone is to couple estrogen with bone-targeting moieties. Conjugation with BP, enables estrogen to
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display a preferential profile in the bone, compared to a natural estrogen analog (17β-oestradiol). Therefore, targeted estrogens could potentially improve the compliance of osteoporosis patients by
reducing the medication frequency, as well as adverse effects (Tsushima, et al., 2000). Selective estrogen receptor modulators (SERMs) are derived from estrogen by medicinal chemistry approaches. Commercialized products, such as Raloxifene and Bazedoxifene, are emerging as relatively new classes of drugs for osteoporosis treatment. Interestingly, SERMs have an agonistic effect similar to that of estrogens in tissues, such as the bone, but an antagonistic or neutral outcome in other tissues, like the breast and uterus (Riggs & Hartmann, 2003). From this
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perspective, SERMs themselves already have a targeting property attributed to the different cell responsiveness and their modulation of nuclear receptors instead of spatial targeting (Shang & Brown, 2002).
Unlike antiresorptive therapy, anabolic therapy, another typical modality for osteoporosis treatment, primarily enhances bone formation rather than reduce bone resorption. PTH is a
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f
representative anabolic drug that has been approved for treating postmenopausal osteoporosis. Despite its better short-term efficacy, compared to BPs, PTH remains only second-line therapy
pr
due to its considerable side effects (e.g., hypercalcemia) and inconvenient dosing (Neer, et al.,
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2001). There is an indication that hypercalcemia is avoidable, and reduced injection frequency is
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possible if PTH targeting strategies are developed. Generally, this targeted system is constructed by fusing PTH with CBD. Ponnapakkam et al. (Ponnapakkam, et al., 2014) demonstrated that
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PTH-CBD increased spinal BMD by 14.2% after 5 months without inducing hypercalcemia
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following monthly injections in ovariectomized rats. PTH-CBD also increased the level of ALP in
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serum, which is consistent with its anabolic effect. Even for a single subcutaneous administration, PTH-CBD showed a sustained bone anabolic effect for an extended period (9–12 months) with no
hypercalcemia (Ponnapakkam, et al., 2012).
PTH aside, the prostaglandin hormone, PGE2, shows an anabolic activity as well and can stimulate in vivo bone growth (Jee, Ke, & Li, 1991). Four receptor subtypes (EP1, 2, 3, and 4) interact with PGE2. Of the four receptor subtypes, EP4 plays a crucial role in the bone-forming
activity of PGE2. There is evidence that activating the EP4 receptor can suppress the apoptosis of osteoblasts and osteoid precursor cells in bone marrow (Machwate, et al., 2001). However, both 35
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PGE2 and EP4 agonists have several side effects, including gastrointestinal disturbance and vasodilation. To avoid drawbacks and realize a sustained and concentrated impact in the bone, the EP4
receptor
agonist
is
conjugated
with
alendronic
acid
via
a
cleavable
dipeptide-para-aminobenzyl alcohol linker. This prodrug has synergistic bone-forming effects through the EP4a and inhibition of resorption by alendronic acid, possessing a significant potential
oo
f
to treat osteoporosis (Xie, Chen, & Young, 2017).
Stem cell therapy could potentially reduce the susceptibility of fracture and increase mineral
pr
density by differentiating into osteoblasts, which would be promising for the treatment of
e-
osteoporosis (Antebi, Pelled, & Gazit, 2014). Allogeneic MSCs isolated from the bone marrow
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have been infused systematically into mice with dexamethasone-induced osteoporosis in the past, with the transfused MSCs homing and inhabiting in the recipient bone marrow for more than 4
(Sui, et al., 2016). Gene engineering is usually used for MSC modification to
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osteoblastogenesis
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weeks. These donor cells committed to Osterix (Osx)+ osteoblast progenitors and induced
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enhance its functionality for tissue regeneration. Li and coworkers (Li, et al., 2016) constructed baculovirus-engineered MSCs expressing miR-140* or miR-214 sponges. These hybrid vectors
transfected MSCs continuously attenuated the cellular levels of miR-140*/miR-214, promoting osteogenesis and repressing osteoclast maturation in vitro. Compared with miR-140*, reducing miR-214 displayed more potent effects. In an osteoporotic rat model, the allotransplantation of miR-214 sponges-expressing MSCs promoted bone healing, remodeling and bone quality (BMD, trabecular thickness, trabecular numbers, and trabecular distance) after 4 weeks.
5.2. Osteosarcoma and bone metastasis 36
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A malignant bone tumor is a highly aggressive tumor that induces destructive changes in the bone structure and causes severe bone pain and other skeletal events. Generally, aggressive bone tumors are classified into primary malignancies (e.g., osteosarcoma) and adaptive bone metastases from other malignant tumors. Osteosarcoma
f
Osteosarcoma, the most common type of primary sarcoma in the bone, is characterized by the
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presence of stromal cells that can generate bone-like tissues (Abarrategi, et al., 2016). Standard
pr
chemotherapy is used customarily as a first-line treatment and has improved the long-term overall
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survival of patients. However, owing to the rigidity, low blood flow, and reduced permeability of
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skeletal tissues, a high dose of chemotherapeutic agents that would cause considerable toxicity is
required (Li, et al., 2016). A more efficient approach is to develop bone-targeted strategies.
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Kopecek and co-workers (Low, Yang, & Kopecek, 2014) utilized D-ASP octapeptide and
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doxorubicin (DOX) to create bone-targeted micelles as potential osteosarcoma therapeutics. The
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micelles displayed rapid adsorption toward HA and potential cytotoxicity to osteosarcoma Saos-2 cells. Integrin avβ3 and avβ5 are expressed widely in osteosarcoma cells. RGD, a cell affinitive peptide, can interact with these integrins and, thus, be used for targeting osteosarcoma. On this basis, Fang et al. (Fang, et al., 2017) developed RGD-decorated biodegradable polymeric micelles loaded with DOX and used them to target MG63 osteosarcoma cells specifically, which resulted in higher cytotoxicity than that obtained with the use of their non-targeted counterparts. Folate receptors are also overexpressed on the surface of osteosarcoma cells. Liposome-packaging
antineoplastic agents (curcumin and C6 ceramide) were modified with folic acid in another
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research to bind with folate receptors, and the targeting liposomes displayed enhanced cell cytotoxicity in osteosarcoma-ridden cells (Dhule, et al., 2014). Osteosarcoma often occurs in the distal femur, proximal humerus, and proximal tibia, all areas with abundant blood supply. This bone tumor depends on the development of new blood vessels, in a process known as angiogenesis, for growth and metastasis (Xie, Ji, & Guo, 2017).
f
Vascular endothelial growth factor (VEGF) is a key tumor-derived angiogenic factor that can
oo
stimulate angiogenesis while increasing vascular permeability, facilitating tumor progress (Quan
pr
& Choong, 2006). Besides, the VEGF level correlates with poor prognosis in osteosarcoma
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patients (DuBois & Demetri, 2007). Thanks to the advancement in biotechnology though, VEGF
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receptor tyrosine kinase inhibitors (TKIs), the most typical anti-angiogenesis targeting therapy,
have been developed successfully and used to treat sarcoma in the clinic. Although T KIs have not
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been applied in clinical osteosarcoma, clinical trials have shown promising outcomes. The Italian
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Sarcoma Group conducted a phase II trial using sorafenib to treat relapsed and unresectable
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osteosarcoma and showed that TKI-targeting therapy increased the 4-month progression-free survival from < 30-46% (Grignani, et al., 2012). There is evidence that several VEGF subtypes are involved in the VEGF family, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and VEGF-F (Niu & Chen, 2010). Among them, the pathway mediated by VEGF-A and VEGF receptors plays a vital role in the pro-angiogenic function of tumors and is prioritized for developing anti-angiogenic therapy. Liang et al (Liang, et al., 2017) utilized CRISPR/Cas9, a powerful genome editing technology, to
generate CRISPR/Cas9 plasmids encoding VEGF-A gRNA. The researchers then screened a cell-specific aptamer (LC09) to improve tumor-targeted characteristics and subsequently 38
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fabricated an LC09-functionalized PEG-PEI-Cholesterol lipopolymer encapsulating CRISPR/Cas9 plasmids for anti-angiogenesis therapy. This system decreased the expression and secretion of VEGF-A, as well as angiogenes is by effective VEGF-A genome editing in osteosarcoma, inhibiting both primary tumor and lung metastasis. miRNA-based therapy has emerged as an attractive strategy in osteosarcoma treatment
f
because of the critical role of miRNA in tumorigenesis and growth. Reportedly, upregulating
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miR-132 can inhibit the proliferation of osteosarcoma cells by arresting the cell cycle at the G1/S
pr
phase, which is mediated by reducing cyclin E1 expression (Wang, et al., 2014). Besides,
e-
miR-133a possesses an antitumor effect by decreasing the proliferation and promoting the
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apoptosis of osteosarcoma cells, a role probably attributed to the suppressed expression of B-cell
lymphoma-extra large (Bcl-xL) and myeloid cell leukemia-1 (Mcl-1) (Ji, et al., 2013). In a recent
al
study, the loss of miR-34a, miR-93, and miR-200c was revealed to occur during tumor switch
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from avascular dormancy to the fast-growing angiogenic phenotype. Subsequently, dendritic
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polyglycerol nanopolyplexes were designed to package these miRNAs for targeting osteosarcoma. After reconstituting the miRNAs into osteosarcoma cells using nanopolyplexes, they were found to reduce angiogenetic factors and cell migration, including their target gene levels, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, thereby prolonging the dormancy period of progressive osteosarcomas (Tiram, et al., 2016). Given that osteosarcoma cells possess osteoblastic features, targeting osteoclast functions could be a potentially useful approach to treat osteosarcoma (Zhou, et al., 2014). ZOL, a member
of BPs, has shown a good affinity for bone tissue. Moreover, ZOL can reduce tumor-induced osteolysis by inhibiting osteoclasts directly and attenuating the expression of RANKL and 39
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monocyte chemoattractant protein-1. These potential outcomes are in line with the significant suppression of in vivo tumor growth (Ohba, et al., 2014). With the advancement in gene engineering, it is convenient to engineer T cells genetically with tumor-associated antigens for immunotherapy. The human epidermal growth factor receptor (HER2) is a kind of oncogene expressed in around 60% of primary osteosarcoma. Ahmed and
f
colleagues’ (Ahmed, et al., 2009) adoptive transfusion of HER2-specific T cells induced
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regression of established osteosarcoma xenografts and increased the overall survival of
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tumor-bearing mice. In a follow-up study, the HER-2-specifc CAR T cells targeted drug resistant
e-
tumor-init iating cells (TICs) and remarkably reduce TICs in bulk tu mors (Rainusso, et al., 2012).
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However, during the pathogenesis, progression and metastasis of osteosarcoma, there is a high
incidence of alterations in genetic information, causing tumor heterogeneity and therapeutic
al
obstacles (Wang, et al., 1998). Identifying and targeting mutated genes in osteosarcoma could
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boost the efficiency of cancer treatment. TP53 gene is a common mutant tumor suppressor gene in
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osteosarcoma and its mutation would lead to the loss of the tumor suppressor function of wild-type TP53 (Duffy, Synnott, & Crown, 2017). Tang et al. (Tang, et al., 2019) used a CRISPR-Cas9 system and a TP53 inhibitor (NSC59984) to knock-out mutant TP53 in osteosarcoma cells with specificity. Following the inhibition of mutant TP53, the migration, pro liferat ion, and tumor formation activity of osteosarcoma cells decreased efficiently. Moreover, the knockout of mutant TP53 reduced the level of oncogene (IGF-1R), anti-apoptotic proteins (Bcl-2), and Survivin in osteosarcoma cells.
Bone metastasis
Bone metastasis, which occurs in 70 % to 80 % of patients, is common in patients with aggressive cancer, especially prostate and breast cancers (Coleman, 2006). In the skeleton, 40
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multi-step processes are involved in metastasis development. Tumor cells need to disseminate from the primary site, colonize and survive in the new microenvironment, escape from dormancy to proliferation state, and eventually grow uncontrollably (Croucher, McDonald, & Martin, 2016). Tumor metastasis in the bone would cause unbearable pain, pathologic fracture, spinal cord compression, and hypercalcemia, significantly reducing the quality of life of patients (Pentyala, et
f
al., 2000). With the advancement in precision medicine, new approaches and therapies have been
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developed to alter the course of bone metastasis. In a real-world setting with the use of
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bone-targeted denosumab among patients with metastatic tumors, greater compliance and longer
e-
persistence were observed, indicating that targeted therapy may improve treatment efficacy,
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meaning that it holds significant potential for the treatment of bone metastasis (Qian, Bhowmik,
Kachru, & Hernandez, 2017).
al
Prostate cancer is one of the most common malignancies and ranks as the second leading
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cause of cancer-related deaths in men (Siegel, Miller, & Jemal, 2019). What is worse, almost 80%
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of patients develop aggressive bone metastasis, substantially reducing expected overall survival to less than 1 year (Cheville, et al., 2002). Unlike other cancer types, the initial metastasis of prostate cancer is limited to the skeleton that is often the only spread site in the late stage. Targeted therapy is promising in the way it controls bone metastasis owing to its unique characteristic of focusing on a given area. As the most abundant component in the bone, the bone matrix also contributes to initiation and support of cancer metastasis in the bone. Converting the bone matrix to a less favorable environment for metastatic tumor cells could be a potentially rewarding treatment
strategy.
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The systemic administration of radiopharmaceuticals has a long history of alleviating bone metastasis. The FDA has approved Strontium-89 (Porter, et al., 1993) and samarium-153 (Sartor, et al., 2004) for commercialized use in treating metastatic prostate cancer, and these substances have shown preferential uptake in areas with high bone turnover, such as metastatic lesions, resulting in improved clinical outcomes in patients with bone metastasis. Besides, rhenium-186, Sr, and rhenium-188 all show a satisfactory effect on palliating bone metastasis in clinical trials.
f
89
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Another radiopharmaceutical radium-223 exhibits delayed symptomatic skeletal events, improved
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pain control, favorable toxicity profile, and a remarkable overall survival benefit in men with
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metastatic prostate cancer (Blacksburg, Witten, & Haas, 2015). In a phase II study of patients with
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hormone-refractory prostate cancer and bone pain, radium-223 treatment prolonged the median
time of prostate-specific-antigen progression to 26 weeks compared to 8 weeks for placebo.
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Moreover, the median overall survival was 65.3 weeks for radium-223-treated patients while that
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for the placebo group was shorten to 46.4 weeks (Nilsson, et al., 2007).
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The metastasis of prostate cancer to the bone is more likely to be osteoblastic instead of lytic, indicating that inhibiting the increased bone deposition by osteoblasts could be an appealing therapeutic option. Endothelin-1 (ET-1), a potent vasoconstrictor, can stimulate osteoblasts into phenotypes of osteoblastic bone lesions in metastatic prostate cancer (Nelson, et al., 1995). Based on these findings, antagonizing ET-1 is considered a promising therapy. In 2018, a phase III clinical trial (SWOG S0421) introduced a strategy combining chemotherapeutic docetaxel with an ET-1 antagonist (Atrasentan) to treat metastatic castration-resistant prostate cancer. Though no
significant difference was found, the therapy with Atrasentan showed 44.0% pain palliation and
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28.7% functional status compared to 41.7% and 24.2% in the control group, respectively (Unger, et al., 2017). According to the microscopic analysis of skeletal metastatic foci, bone resorption mediated by osteoclasts could prime the bone for osteoblastic metastasis. Hence, targeting osteoclasts could serve as an alternative approach to control metastasis development. BPs, with a high affinity for
f
the skeleton and an excellent ability to inhibit osteoclast activity, have been used in metastatic
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cancer treatment. Notably, zoledronate has been approved for treating bone metastases of prostate
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cancer in the clinic. Because the RANK/RANKL/OPG signaling pathway is essential for
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osteoclast-mediated bone resorption, using OPG-Fc containing an OPG binding domain could
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block the RANK pathway from activating osteoclasts, suppressing the growth of metastatic
tumors (Yonou, et al., 2003).
al
Breast cancer, which is the most common cancer type in women, invades distant organs
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preferentially, especially the bone. Killing tumor cells in the bone directly is an effective way of
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treating metastatic cancer. Cytotoxic chemotherapeutics can cause cytotoxicity to tumor cells and attenuate metastatic tumor progress. However, low selectivity and high dose-related toxicity have
restricted the therapeutic efficacy of these drugs significantly. Reportedly, nanotechnology and bone targeting moieties could help resolve this dilemma to some extent. Zhou et al. (Zhao, et al., 2019) used Glu6 -RGD as a targeting ligand to fabricate liposomes loaded with paclitaxel, which showed extraordinary targeting activity on metastatic cancer cells, inducing higher cytotoxicity. Similarly, Liu’s group (Zhu, et al., 2018) developed a class of ALN-functionalized micelles encapsulating bortezomib-catechol conjugates, and this prodrug showed an acid-responsive drug
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release performance and minimized systematic toxicity. Moreover, this targeted platform remarkably suppressed the growth of cancer cells at metastatic bone lesions and decreased the destruction of the metastatic bone structure.
As described above, osteoclasts play an essential role in bone metastasis from primary tumors. A therapeutic modality simultaneously working on bone resorption and tumor growth
oo
f
could be a meaningful strategy to treat breast cancer-related bone metastasis. ALN-modified polymer nanoparticles have been fabricated to package cisplatin prodrugs to treat bone metastasis
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originating from breast cancer. This platform not only inhibited tumor growth in the bone
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effectively but also decreased osteoclastic bone destruction efficiently (He, et al., 2017).
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ALN-functionalized nanoparticles have similarly been developed to load DOX and have shown suppressed tumor growth and reduced bone resorption with negligible systematic toxicity (Zhao,
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5.3. Osteoarthritis
rn
al
et al., 2017).
Osteoarthritis is a degenerative and heterogeneous joint disease that can cause pain, stiffness, and even disability to patients. Specifically, this “joint disorder” is characterized by articular
cartilage degradation, subchondral bone sclerosis, osteophyte formation, and synovial inflammation (Herrero-Beaumont & Roman-Blas, 2013). Several targeted approaches have been explored in osteoarthritis treatment based on the development and features of osteoarthritis.
Increasing evidence shows that subchondral bone remodeling hightens during the progression of osteoarthritis (Bellido, et al., 2010; Goldring & Goldring, 2010), and this subchondral bone 44
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resorption usually occurs in the early phase of osteoarthritis development. Hence, inhibiting osteoclastic bone resorption could be a potentially useful therapeutic option. With a critical role in bone turnover, BPs can serve as both targeting moieties and efficient therapeutic agents, providing benefits
for
osteoarthritis
treatment.
Moreau
and
colleagues
found
that
tiludronate
(TLN) treatment resulted in less joint effusion, reduced level of PGE2 in synovial fluids, and
f
larger subchondral bone surfaces when compared with placebo controls. TLN also decreased
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inflammatory factors, including matrix MMP-13 and ADAMTS5 in cartilage and cathepsin K in
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the subchondral bone, further alleviating the symptoms of osteoarthritis (Mor eau, et al., 2011).
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Alongside preclinical investigations, BPs display promising outcomes in clinical application.
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According to annually collected patient data from the NIH Osteoarthritis Initiative cohort over 4
years, BP users had lesser joint space narrowing over time (Laslett, et al., 2014).
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Repetitive mechanical injury is a vital signal for the occurrence and progression of
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osteoarthritis. Chondrocytes are generally accepted as the target of these abnormal biomechanical
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factors, making them ideal targets for osteoarthritis treatment (Goldring, 2000). Pi et al. (Pi, et al., 2011) identified a chondrocyte-homing peptide (CAP, DWRVIIPPRPSA) with a two-step
biopanning using synovium and cartilage explants from healthy rabbits and conjugated this CAP covalently with polyethylenimine (PEI) to construct a non-viral vector. The PEI-CAP copolymers were then used to condense siRNA in nanoparticles to silence hypoxia-inducible factor-2α, a key factor in chondrocyte catabolic state. The cartilage-targeting nanoparticles downregulated catabolic
factors in vitro, maintained cartilage integrity, and alleviated synovium inflammation in vivo (Pi, et al., 2015).
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NF-κB signaling pathways are involved extensively in inflammatory diseases and play an essential role in subchondral bone resorption. Notably, synoviocytes and chondrocytes secrete pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), which trigger osteoblasts to release RANKL to bind with RANK. NF-κB transcription factors are then activated for subsequent bone resorptive activity (Rigoglou, Papavassiliou, & biology, 2013). Therefore, targeted therapies
f
inhibiting NF-κB pathways could be acceptable approaches to treat osteoarthritis. In a
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staphylococcus aureus-induced osteoarthritis model, combinational therapies, composed of
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antibiotics with RANK-Fc or OPG-Fc, reduced the expression of bone resorption makers,
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including osteocalcin, the C-terminal telopeptide of type I collagen, and TRACP5b, mitigating
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cartilage/bone destruction (Verdrengh et al., 2010). To block the NF-kB signaling pathway further
and accurately, Doschak et al. (Doschak et al., 2009) conjugated OPG with BP chemically, and
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after systemic administration, OPG-BP conjugates accumulated highly in the bone, suggesting that
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they could, potentially, be applicable in the treatment of osteoarthritis with active bone
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remodeling.
5.4. Bone fracture
Bone fractures pose major challenges to orthopedic practice. Around 5-10% of fractures result in delayed healing o r non-union (Novicoff, et al., 2008). Despite the fact that autologous bone graft is regarded as a gold-standard treatment in fracture non-union, their application can lead to donor site morbidity (Kneser, et al., 2006). Alternatively, recombinant human bone morphogenetic protein (rhBMP)-2 and rhBMP-7 are used for bone harvesting. However,
rhBMP treatments have a very narrow indication and require megadoses of the protein (Virk 46
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& Lieberman, 2012). With the latest signs of progress made in cell and molecular biology, more
effective modalities are developed to restore the structural integrity of bone.
As previously mentioned, MSCs can traffic to injured tissues and differentiate into the osteoblasts and chondrocytes for bone healing. Therefore, MSC-based cell therapy could serve as a potential strategy in fracture repair. Reportedly, the concentration and counts of injected MSCs
oo
f
are in proportion to the healing rate. A practical investigation showed that the fracture of patients who received less than 1000 MSCs per mL and total 30,000 MSCs did not heal, whereas those of
e-
pr
patients given 1500 MSCs per mL and total 54,000 MSCs healed (Gomez-Barrena, et al., 2015).
Although MSCs have extraordinary performance in tissue engineering, their differentiation
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and homing ability remain limited for efficient bone regeneration. To improve this condition, Xu
al
et al. (Xu, et al., 2015) developed Sry-related high-mobility group box 11 (Sox11)-modified
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MSCs by transducing lentivirus carrying Sox11 into MSCs for fracture healing. The results
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demonstrated that the overexpression of Sox11 enhanced the BMP/Smad signaling pathway and activated the promoter activity of Run x2 and CXCR4. Co mpared with control MSCs, more So x11-overexpressed MSCs migrated to the fracture area, initiated callus ossification, and promoted fracture healing in an open femur fracture model. Salvianic acid A (SAA) is a water-soluble active
compound extracted from salvia miltiorrhizae (Danshen), which has potent anabolic ability (Cui, et al., 2009). However, the clinical translation of SAA is greatly impeded by its short half-life in serum and its lack of osteotropicity. To deal with these conditions, Liu et al. (Liu, et al., 2018)
develop a bone-targeting liposome formulation to deliver SAA specifically to the bone. The author synthesized pyrophosphorylated cholesterol by conjugating pyrophosphate to cholesterol via a 47
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triethylene glycol linker and used it as the targeting ligand. The SAA-loaded liposomes were then
prepared using a reverse-phase evaporation method with pyrophosphorylated cholesterol and lecithin as the backbone. The targeted-liposome formulation showed a high affinity for HA in vitro and robust ability of bone-targeting and long retention in vivo. In a delayed femur fracture union mouse model, SAA-loaded targeting liposome was found to shorten healing time
f
remarkably (from > 64 days to 42 days), improve histologic and histomorphometric parameters
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and mechanical property outcomes.
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5.5. Other bone-related diseases
Apart from the skeletal maladies mentioned above, several other bone-related conditions also
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benefit from targeted therapy. PDB is a common skeletal disorder with increased and inordinate
al
bone remodeling, leading to osteolytic and osteosclerotic lesions (Vallet & Ralston, 2016). BP is
rn
one of the first-line medications for treating PDB because of its extraordinary inhibitory effects on
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bone turnover and innate bone affinity. Reportedly, the RANKL/OPG ratio in serum lessened after BP treatment, decreasing subsequent bone resorption and attaining highly efficient PDB therapy (Martini, et al., 2007).
Corticosteroids are routinely used to treat inflammatory and autoimmune diseases but their use is limited by steroid-associated osteonecrosis (SAON), a severe complication that often induces subchondral bone destruction (Chan, et al., 2006). Chen et al. (Chen, et al., 2018) developed a class of Asp8-functionalized liposomes loaded with a small phytomolecule (icaritin) for SAON prevention and found that liposomes alleviated steroids-treated rats of SAON
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efficiently, with remarkably decreased osteocyte apoptosis, as well as increased osteoclastogenesis and osteogenesis.
Osteomyelitis is an inflammatory disease accompanied by severe bone destruction (Lew & Waldvogel, 2004). Current therapy for osteomyelitis focuses mainly on antimicrobial issues. However, even therapeutic efficiency in these instances is usually restricted by the limited
oo
f
concentrations of antibiotics that reach the bone. Promisingly, Sedghizadeh and coworkers have established an osteoadsorptive BP-ciprofloxac in conjugate that demonstrates a significantly
pr
improved therapeutic index in osteomyelitis treatment compared to ciprofloxacin (Xie, et al.,
6. Conclusion and perspectives
Pr
e-
2017).
al
In this review, we summarized the recent progress in bone-targeted therapy. Targeted therapy
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for bone-related diseases has several advantages over standard treatment procedures. Therapeutic
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agents are concentrated in the targeted skeleton to a maximum extent, decreasing the required dosage significantly, and promoting the therapeutic efficacy of the agents. Additionally, the retention time of the drugs is prolonged in the targeted area with improved bioavailability.
Furthermore, the systematic toxicities of these agents are substantially reduced in the controlled non-specific and unintended distribution to other tissues. We also presented the composition of skeletal tissues, including the extracellular matrix and cells, in detail. With the understanding of bone biology, we next summarized the commonly used bone-targeting moieties, with emphasis on BPs, TCs, and biomimetic proteins and peptides, as well as targeting strategies in the bone. Lastly,
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we discussed the potential application of targeted therapy in the treatment of bone-related diseases. It appears that a targeting strategy is a promising approach to skeletal disease treatment.
Though the existing targeted therapy has so far been a hugely promising success, there are still considerable obstacles that hinder its practical application. Unlike other soft tissues, the bone is characterized by its rigidity, low permeability, and reduced blood flow, features that limit the
oo
f
reach of most of the current targeting moieties, such as receptors and biomolecules, to the bone. However, bits of existing targeting moieties that do reach the bone are slowly or even hardly
pr
cleared from the body, which would cause long-term safety concerns. Moreover, most of the
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targeted therapies are still at laboratory phases of investigations, and researchers are finding it
Pr
challenging to advance them to the clinical stage. Therefore, more researches need to be made to resolve the dilemma faced in the use of bone-targeted therapy. With a comprehensive
al
understanding of bone biology and the rapid development of biotechnology, it is possible to
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explore more effective moieties to target the skeleton in the future. Potential options are now in
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the numbers, meaning that the suboptimal targeting moieties could be substituted by safer ones. Furthermore, clinical translations could be accelerated using advanced development in genomics,
genetics, and cell biology. Exploiting effective models to minimize the physiological differences between animals and humans may also shorten the period between the basic research and clinical application. Nevertheless, targeted therapy has various merits, exhibits satisfactory benefits, and could be an appealing strategy in bone-related disease treatments.
Conflicts of interest The authors declare that there is no conflict of interest. 50
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Acknowledgements This work was supported financially by the National Natural Science Foundation of China [Grant
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Pr
e-
pr
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f
number: #81672216, #81874026]
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Table 1. Summary of bone cells
Cell type
Osteoblasts
Resources
MSC lineage
Ref
Cuboidal shaped cells with plenty of rough endoplasmic reticula, well-developed Golgi apparatus, and diversified secretory vesicles
Bone-forming abilities through the deposition of the organic matrix and participation in subsequent bone mineralization
f o
(Marks & Popoff, 1988; Florencio-Silva, et al., 2015; Burr, 2019; Yadav, et al., 2016)
Reacquire secretory abilities; Prevent direct contact between bone matrixes and osteoclasts and participate in osteoclast differentiation
(Matic, et al., 2016; Miller, et al., 1989; Hienz, Paliwal, & Ivanovski, 2015)
Resorb fully mineralized bones
(Detsch & Boccaccini, 2015; Teitelbaum, 2000; Merolli, et al., 2018)
Permit the diffusion of mineral and fluids; Detect mechanical pressures; Regulate osteoblasts and osteoclasts
(Sommerfeldt & Rubin, 2001; Shea & Miller, 2005; Rochefort, Pallu, & Benhamou, 2010; Mori & Burr, 1993; Prideaux, Findlay, & Atkins, 2016)
l a n
Osteoblasts
o r p
e
r P
r u o
Hematopoietic stem cell lineage
J Osteocytes
Functions
Flat-shaped cell with extremely flat nuclei and few cytoplasmic organelles
Bone lining cells Inactive osteoblasts
Osteoclasts
Structure
Polarized and multinucleated giant cells
A dendritic morphology with a higher number of filopodia
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Table 2. Summary of bone-targeting moieties
Classifications
BPs
Targeting moieties
Targeting site
BPs
TCs
Biomimetic bone-targeting moieties
Acid oligopeptides composed of repeating Asp or Glu
J
HA
References
Induce atypical femur fractures; Osteonecrosis of the jaw; Target HA surface; Shift bone Gastrointestinal effects; Cancer of homeostasis toward bone esophagus and atrial fibrillation; formation; Induce osteoclast Inhibit bone mineralization and apoptosis induce osteomalacia, typical acute-phase response and renal failure at high dose
(Yewle, 2012; Lawson, et al., 2010; Drake, Clarke, & Khosla, 2008; Dell, et al., 2012; Khan, et al., 2015; Adami & Zamberlan, 1996)
Target skeletal tissues; Have broad spectrum antibiotic activity; Reduce bone resorption; Label the surface of growing bone formation area
Cause inherent biological activity including heartburn, rash, dizziness, hypoglycemia and nausea; Stain teeth in dental developing children; Being chemical unstable; Induce enamel hypoplasia during calcification at a high dose
(Albert & Rees, 1956; Reichert, et al., 2012; Nakamura, et al., 2000; Valentín, et al., 2009; Bevelander, Rolle, & Cohlan, 1961)
Have good affinity toward HA
Poorly stable to enzymatic cleavage; Low oral bioavailability; Complicated production process;
(Yarbrough, et al., 2010; William N, 2010; Tulasi, 2011,
al
o r p
e
r P
rn
u o
HA
limitations
f o
HA
TCs
Bioactivities
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(AspSerSer)6
VTK
HA
CBD
Collagen
Produce targeting
Osteocalcin
HA
Bind to HA; Prevent the growth of crystal
BSP
Osteoblasts, fibroblasts, collagen
Target osteoblasts, fibroblasts and collagen; Initiate the nucleation of HA crystal
Osteopontin
HA
MSCs
Injured bone
l a n
r u o
J
Other moieties
Chelate with osteoblast-mediated mineralizing nodules and amorphous calcium phosphate Target HA and skeleton-like materials
Bone formation surface
fusion-protein
Harsh conditions for transport and storage
f o
for
Ryuichi Fujisawa, 2012; Hunter & Goldberg, 1993; Boskey, 1995; Aoki, et al., 2012; Kitaori, et al., 2009)
o r p
e
r P
Bind to the surface of HA; Inhibit the formation and growth of crystal Home to fractured sites in bone 2+
HA
Chelate with Ca on skeletal tissues; No effect on bone metabolism
Long-term safety concerns
(Lange, et al., 2016)
CH6 aptamer
Osteoblasts
Target osteoblasts
High cost; Complicated production process
(Liang, et al., 2015)
Radionuclides
HA
Deposit in bone and partic ipate in metabolic process of bone Long-term safety concerns minerals
Phosphonate-containing compounds
54
(Cawthray, et al., 2015)
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Table 3. A brief summary of targeted therapy for bone-related diseases
Bone diseases
Osteoporosis
Osteosarcoma
Bone metastasis
Therapeutics
Targets
Effect
Reference (Ryu, et al., 2016) (Riggs & Hartmann, 2003) (Ponnapakkam, et al., 2012) (Xie, Chen, & Young, 2017)
ALN-NDs
Osteoclasts
Accumulate in bone and possess potential to treat osteoporosis
SERMs
Osteoclasts
Targeted therapy for osteoporosis
PTH-CBD
Osteoblasts
Has high bone affinity and sustained
Alendronic acid-conjugated EP4 receptor agonist
Osteoblasts
Bone-targeting and synergistic bone forming effects
RGD-decorated micelles
Osteosarcoma cells
Induce higher cytotoxicity to tumor cells
Injured bone
Promoted bone healing, remodeling and bone quality (BMD, trabecular thickness, trabecular numbers, and trabecular distance)
(Li, et al., 2016)
Decrease VEGF expression and inhibiting tumor growth
(Liang, et al., 2017)
Reduce factors for angiogenesis and cell migration
(Tiram, et al., 2016)
Baculovirus-engineered MSCs LC09 aptamer-functionalized lipopolymers MicroRNAs-packaged nanopolyplexes Mutant TP53 knockout CRISPR-Cas9 system ZOL
l a n
J
r u o VEGF
ro
miRNA in osteosarcoma Mutant TP53
Osteoclasts
Radium-223
Bone matrix
OPG-Fc
Osteoclasts
f o
p e
anabolic effect
r P
Inhibit the migration, proliferation, and tumor formation activity of osteosarcoma cells Reduce tumor-induced osteolysis Improve the symptomatic skeletal events and pain control as well as reducing toxicity Block RANK pathway and inhibit metastatic tumor 55
(Fang, et al., 2017)
(Tang, et al., 2019)
(Ohba, et al., 2014) (Blacksburg, Witten, & Haas, 2015) (Yonou, et al., 2003)
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Glu6-RGD-decorated liposomes ALN-modified nanoparticles
f o
Tiludronate Osteoarthritis
Metastatic cancer Induce higher cytotoxicity cells Inhibit tumor growth and decrease osteoclastic bone Osteoclasts destruction Subchondral Decrease inflammatory factors and alleviate the symptom of bone osteoarthritis Silence HiF-2α; Downregulate catabolic factors, maintain Chondrocytes cartilage integrity and alleviate synovium inflammation Block RANK/RANKL pathway and induce active bone NF-κB remodeling for osteoarthritis treatment Migrate to the fracture area, initiate callus ossification and Fracture area promote fracture healing Show high affinity for HA; Shorten healing time; Improve Bone matrix therapeutic outcomes
CAP-PEI based nanoparticles
BP-conjugated OPG Sox11-modified MSCs
Bone fracture SAA-loaded liposomes
l a n
o r p
e
r P
PDB
BP
Osteoclasts
SAON
Asp8-functionalized liposomes
Osteomyelitis
BP conjugated ciprofloxacin
Osteocytes and Decrease osteocytes apoptosis and increase osteoclatsogenesis osteoclasts and osteogenesis High turnover Improve the therapeutic index for osteomyelitis site
o J
ur
Reduce RANKL/OPG ratio
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(Zhao, et al., 2019) (He, et al., 2017) (Moreau, et al., 2011) (Pi, et al., 2015) (Doschak, et al., 2009)
(Xu, et al., 2015)
(Liu, et al., 2018) (Martini, et al., 2007) (Chen, et al., 2018) (Xie, et al., 2017)
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References
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Figure 1
Figure 2
Chen Shi, Tingting Wu, Yu He, Yu Zhang, Dehao Fu PII:
S0163-7258(20)30001-2
DOI:
https://doi.org/10.1016/j.pharmthera.2020.107473
Reference:
JPT 107473
To appear in:
Pharmacology and Therapeutics
Please cite this article as: C. Shi, T. Wu, Y. He, et al., Recent advances in bone-targeted therapy, Pharmacology and Therapeutics(2020), https://doi.org/10.1016/ j.pharmthera.2020.107473
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© 2020 Published by Elsevier.
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P&T #23607 Recent advances in bone-targeted therapy Chen Shi a,# , Tingting Wu a,# , Yu He b , Yu Zhang a, Dehao Fu b,* a
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong
University of Science & Technology (HUST), Wuhan, P.R. China Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong
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b
Corresponding author:
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*
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University of Science & Technology (HUST), Wuhan, P.R. China
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Dehao Fu, Department of Orthopaedics, Union Hospital, Tongji Medical College,
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Huazhong University of Science & Technology (HUST), 1277 Jiefang Avenue,
Wuhan 430022, P.R. China. Email: [email protected]
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These authors contributed equally to this work.
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#
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Abstract
The coordination between bone resorption and bone formation plays an essential role in keeping the mass and microstructure integrity of the bone in a steady state. However, this balance can be disturbed in many pathological conditions of the bone. Nowadays, the classical modalities for treating bone-related disorders are being challenged by severe obstacles owing to low tissue
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selectivity and considerable safety concerns. Moreover, as a highly mineralized tissue, the bone
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shows innate rigidity, low permeability, and reduced blood flow, features that further hinder the
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effective treatment of bone diseases. With the development of bone biology and precision
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medicine, one novel concept of bone-targeted therapy appears to be promising, with improved
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therapeutic efficacy and minimized systematic toxicity. Here we focus on the recent advances in
bone-targeted treatment based on the unique biology of bone tissues. We summarize commonly
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used bone targeting moieties, with an emphasis on bisphosphonates, tetracyclines, and biomimetic
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bone-targeting moieties. We also introduce potential bone-targeting strategies aimed at the bone
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matrix and major cell types in the bone. Based on these bone-targeting moieties and strategies, we discussed the potential applications of targeted therapy to treat bone diseases. We expect that this review will put together useful insights to help with the search for therapeutic efficacy in bone-related conditions.
Keywords: Bone targeting, osteoblasts, osteoclasts, bone remodeling, bone formation, bone resorption
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Contents
1. Introduction 2. Bone structure and biology 3. Bone-targeting moieties 4. Bone-targeting strategies
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5. Targeted therapy for bone-related diseases
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6. Conclusion and perspectives
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Conflicts of interest
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Acknowledgements
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References
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Abbreviations
Asp,
aspartic
acid;
ALN,
alendronate;
BMPs,
bone
morphogenetic
proteins;
BPs,
bisphosphonates; BSP, bone sialoprotein; BMD, bone mineral density; CAP, chondrocyte-homing peptide; CBDs, collagen binding domains; CDs, carbon dots; DC, doxycycline; DOX, doxorubicin; ET-1, endothelin-1; Glu, glutamic acid; HA, hydroxyapatite; MMPs, matrix
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metalloproteinases; MSCs, mesenchymal stem cells; OPG, osteoprotegerin; PDB, Paget's disease of bone; PTH, parathyroid hormone; PGE2, prostaglandin E2; PLGA, Poly(lactic-coglycolic
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acid); RANK, receptor activator of NF-κB; SAA, salvianic acid A; SAON, steroid-associated
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osteonecrosis; Sct, Salmon calcitonin; SERMs, selective estrogen receptor modulators; SELEX,
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systematic evolution of ligands by exponential enrichment; TCs, tetracyclines; TKIs, tyrosine
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kinase inhibitors; VEGF, vascular endothelial growth factor; ZA, zoledronic acid.
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1. Introduction
The bone is a specified connective tissue with highly mineralized architecture and structure (Burr, 2019). As an internal support system, the bone provides a structural foundation for the body and sites for muscle attachment for locomotion. Additionally, the bone offers protection to the brain and splanchnic organs, as well as a house for hematopoietic tissues of the bone marrow. The
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bone is also the primary source and depot of inorganic ions, especially phosphate and calcium,
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which can participate actively in mineral homeostasis and energy metabolism in the body
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(Florencio-Silva, et al., 2015). For the healthy development and maintenance of the skeleton, the
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bone undergoes a constant modeling and remodeling process through bone formation by
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osteoblasts and bone resorption by osteoclasts (Low & Kopecek, 2012). Under healthy
physiological conditions, the balance between bone-resorption and rebuilding is well-coordinated,
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which can keep the microstructure integrity and mass of the bone in a steady state. However, this
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equilibrium would be disturbed in many bone diseases (Rodan & Martin, 2000).
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As the most prevalent form of bone metabolic disorders, osteoporosis has a high incidence in women and men over 50, especially postmenopausal women. Osteosarcoma and bone metastasis, other types of imbalances in bone metabolism, could cause significant pain and increase mortality rates in patients. Other diseases, including osteoarthritis, osteomyelitis, and Paget's disease of bone (PDB), could amplify the economic burden and decrease the quality of life for millions of individuals worldwide. With an advanced understanding of bone biology, the treatment of bone diseases has been
improved but still faces significant obstacles in the clinic. Estrogen replacement therapy is usually utilized for osteoporosis in postmenopausal women. However, the treatment remains a source of 5
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considerable concerns after prolonged administration, especially as a potential risk for breast cancer, uterus cancer, and endometritis (Astedt, 1982; Wallach & Gambrell, 1982). Parathyroid hormone (PTH), the most frequently used anabolic, is effective in stimulating bone formation. Unfortunately, the anabolic effect of PTH is only limited to two years, owing to a secondary osteoclastogenic effect that results in bone catabolism over anabolism (Cosman., et al., 2005;
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Neer, et al., 2001). More significantly, patients receiving PTH may also carry an increased risk of
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developing osteosarcoma (Leder, 2017; Lindsay, et al., 1997; Neer, et al., 2001). An RNA
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interference (RNAi)-based therapy aimed at bone disease-associated pathogenic genes offers a
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new genetic medical approach; this therapy is potentially translational therapy for bone-related
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diseases (Novina & Sharp, 2004). However, this modality requires a large therapeutic dose of
systematically administered siRNA, which would increase cost and safety concerns (Itaka, et al.,
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2007). Moreover, the above chemicals or biotherapies are usually administered systematically
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when treating bone-related disorders. On the one hand, the therapeutic agents have a non-specific
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in vivo bio-distribution, causing undesired side effects to non-skeletal tissues. On the other hand, the low concentration of therapeutics in localized bone would maximize therapeutic efficiency (Carbone, et al., 2017). These limitations leave the field with a significant challenge to surmount in the current bone disease treatment strategies. Hence, the development of effective and innovative therapies against bone-related diseases is highly desirable. The most important clinical objective in treating clinical diseases is to realize precise therapeutic efficacy in defined pathological s ites. Specific treatment for bone-related disorders
also inspires abundant interests. Pierce et al (William M. Pierce, 1987) first proposed the concept of ‘bone-targeting’ in 1986, providing new insights into bone diseases. With years of concerted 6
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efforts, targeted therapy has made considerable progress in bone disease treatment (He, et al., 2017; Hirabayashi & Fujisaki, 2003; Sousa & Clezardin, 2018; Zhang, et al., 2018). By endowing bone therapeutic agents with osteotropicity, their pharmacokinetic profile can be altered significantly to a favorable skeletal deposition. This therapeutic regiment in bone tissues would work sustainably and effectively to improve the local therapeutic index (Wang, et al., 2005).
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Besides, the preferential accumulation of therapeutics in the bone can decrease the systematic
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distribution to other tissues, potentially minimizing systemic toxicity and long-term concerns
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remarkably (E. J. Carbone, et al., 2017). Also, the required dose of therapeutic agents in
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bone-targeted therapy for local application is smaller when compared to doses used in traditional
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treatments (Cheng, et al., 2017). Given these unique advantages, bone-targeted treatment could
serve as a promising modality in the therapeutic field of bone diseases.
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In this review, we will focus on the advances in recent findings on bone-targeted therapy
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based on the unique biology of bone tissues. We will strive to introduce the commonly used
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bone-targeting moieties, with emphasis on bisphosphonates (BPs), tetracyclines (TCs), and bone-targeting biologicals. We will also summarize the main bone-targeting strategies aimed at the bone matrix and major cell types, such as osteoblasts, bone lining cells, osteoclasts, and osteocytes in bone tissues. We will then discuss the potential and promising applications of targeted therapy to treat bone diseases, including osteoporosis, osteosarcoma and bone metastasis, osteoarthritis, bone fracture and others based on the bone-targeting moieties and strategies. We hope that this review will provide useful information towards overcoming the current dilemma faced by
bone-related therapies and offer new insights into finding ways to treat bone-related diseases efficiently. 7
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2. Bone structure and biology 2.1. Composition of the bone matrix The composition of the bone varies with its diseases, age, anatomical location, and nutritional status. Generally, an adult bone is composed of an organic matrix (20-40%), inorganic mineral
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(50-70%), water (5-10%), and lipids (1-5%) (Shea & Miller, 2005).
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Organic matrix
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The organic matrix of the bone consists primarily of collagen (approx. 90%), predominantly
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type I collagen, a triple-helical molecule composed of a single alpha-2 chain and two identical
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alpha-1 chains. Collagen is deposited in layers of mature bones, known as lamellae, which endows
the bone tissue with a high density of collagenous filaments. Non-collagenous proteins, such as
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osteonectin, osteopontin, and matrix GLA protein, within the bone matrix, may play a role in the
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matrix mineralization process, while others, like growth factors, bone morphogenetic proteins
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(BMPs), cytokines, and adhesion molecules have important signaling functions (Sommerfeldt & Rubin, 2001). Moreover, proteoglycans, including biglycan, osteoaderin, decorin, and lumican, are also located in the matrix (Florencio-Silva, et al., 2015). Inorganic mineral Bone mineral accounts for 50% and 75% of bone tissue by volume and weight, respectively. The majority of inorganic materials in the bone mineral are calcium and phosphate ions. Significant amounts of sodium, bicarbonate, citrate, potassium, magnesium, zinc, fluorite,
strontium, and barium are also present in the bone (Downey & Siegel, 2006). Notably, calcium and phosphate ions nucleate to form hydroxyapatite (HA) [Ca10 (PO4 )6 (OH)2 ], a plate-like crystal 8
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that is 20-80 nm in length and 2-5 nm in thickness; this crystal can provide strength and rigidity to skeletal load-bearing features. HA also contains many impurities, such as carbonate and magnesium, that cause bone apatite to be crystallized poorly and carbonate substitutes apatite. This imperfection could render apatite more soluble and, thus, enable it to release ions for homeostasis (Shea & Miller, 2005).
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2.2. Bone cell biology
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As a rigid structure, the bone carries a self-repairing ability that can remove and replace
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mineral stores rapidly during metabolic demand and reshape the structure after altering
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mechanical stimuli. Four distinctly different cell types participate in the formation, resorption, and
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maintenance of the bone: osteoblasts, bone lining cells, osteoclasts, and osteocytes (Table 1). Osteoblasts
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Osteoblasts are a group of cells with a cuboidal shape located along the surface of the bone.
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These cells account for 4-6% of total bone cells (Capulli, Paone, & Rucci, 2014). Osteoblasts are
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derived from a mesenchymal stem cell (MSC) lineage and can form a compact layer of cells on the bone surface together with their precursors. Structurally, these cuboidal-shaped cells contain plenty of rough endoplasmic reticula, well-developed Golgi apparatus, and diversified secretory vesicles. These morphological characteristics reflect the protein-synthesizing and secreting activity of these cells (Marks & Popoff, 1988). Functionally, osteoblasts are well known for their prominent bone-forming abilities through the deposition of the organic matrix and participation in subsequent bone mineralization. During this process, osteoblasts first produce collagen,
predominantly type I collagen, non-collagenous proteins (e.g., osteocalcin, bone sialoprotein (BSP) II, and osteopontin), and proteoglycan (e.g., biglycan and decorin) to form an organic 9
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matrix (Florencio-Silva, et al., 2015). Mineralization then takes place in two phases following the organic matrix formation: vesicular phase and fibrillar phase (Burr, 2019; Yadav, et al., 2016). In the vesicular phase, matrix vesicles with variable sizes, ranging from 30 to 200 nm, are released by osteoblasts to the newly formed bone matrix. Osteoblasts then secrete enzymes and alkaline phosphatase (ALP) to release calcium ions from proteoglycan-binding compounds and phosphate
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ions from phosphate-containing compounds, respectively, inside the vesicles, which can further
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form HA crystals (Arana-Chavez, Soares, & Katchburian, 1995). In the fibrillar phase, once the
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calcium and phosphate ions in matrix vesicles supersaturate, their structures are ruptured, and the
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HA crystals diffuse to surrounding matrixes (Boivin, et al., 2008; Silva & Bilezikian, 2015).
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Bone lining cells
Bone lining cells are inactive osteoblasts at the bone surface. These quiescent cells differ
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from active osteoblasts and do not undergo neither bone formation nor resorption.
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Morphologically, bone lining cells are flat-shaped cells with extremely flat nuclei and few
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cytoplasmic organelles that can extend well along the bone surface (Matic, et al., 2016). Depending on the physiological status of the bone, bone lining cells can reacquire secretory abilities, increase in size, and adopt a cuboidal shape (Miller, et al., 1989). When bone resorption does not initiate, these cells prevent direct contact between bone matrixes and osteoclasts and participate in osteoclast differentiation (Hienz, Paliwal, & Ivanovski, 2015). Bone lining cells are also a substantial portion of the temporary anatomical structure noted as the basic multicellular unit during the bone remodeling process (Everts, 2002).
Osteoclasts
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Osteoclasts are polarized, multinucleated giant cells that originate from hematopoietic stem cell lineage. The most important characteristic of osteoclasts is their ability to resorb fully mineralized bones (Detsch & Boccaccini, 2015). Resorption begins with the activation of osteoclasts, which requires osteoclasts to attach to the bone surface (Teitelbaum, 2000). Bone resorption then occurs in a particular invaginated cell specialization zone known as the “ruffled
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border,” the site of proteolytic enzyme and acid release for matrix degradation and mineral
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dissolution (Merolli, et al., 2018). Subsequently, the degraded matrix and mineral byproducts are
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transported to the extracellular environment at the opposite side of the cells from the ruffled
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border. After the degradation process, osteoclasts either become inactive or directly die via cell 3
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apoptosis. Generally, an activated osteoclast can complete 200,000 µm worth of resorption per
day, which is nearly equal to the bone formation rate by 7 to 10 generations of osteoblasts with a
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15 to 20 days lifespan (Sommerfeldt & Rubin, 2001). Reportedly, osteoclasts also possess other
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Osteocytes
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functions, such as the direct regulation of the hematopoietic stem cell niche (Julia F, 2014).
As the most abundant and long-living cells in bone cell populations, osteocytes comprise 90% to 95% of all bone cells and have an extremely long lifespan of up to 25 years (Franz-Odendaal, Hall, & Witten, 2006). Osteocytes are derived from MSCs through the differentiation of osteoblasts. Though the precise mechanisms of how osteoblasts become osteocytes remain elusive, it is believed that an embedding mechanism may explain the transmission process. Compared to neighboring cells, a subpopulation of osteoblasts on bone
surface slow down their matrix production and then become “buried alive” in the mineralized matrix produced by adjacent osteoblasts (Franz-Odendaal, Hall, & Witten, 2006). After 11
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transmission, osteocytes display distinctly different structures and functionalities. Compared to osteoblasts, osteocytes have a smaller size, increased nucleus to cytoplasm ratio, and fewer cell organelles. Osteocytes also show a dendritic morphology with a higher number of filopodia (Sommerfeldt & Rubin, 2001). Though they cannot achieve bone formation directly like osteoblasts, they have several important roles. Typically, osteocytes can permit the diffusion of
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mineral and fluids, helping to maintain bone mineral homeostasis (Shea & Miller, 2005).
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Additionally, osteocytes can detect mechanical pressures and serve as mechanosensors, promoting
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the adaptation of the bone to daily mechanical forces (Rochefort, Pallu, & Benhamou, 2010). This
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Prideaux, Findlay, & Atkins, 2016).
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cell type can also regulate the activities of both osteoblasts and osteoclasts (Mori & Burr, 1993;
The interconnection between bone cells and matrix in bone microenvironment
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It has been suggested that the crosstalk between bone cells should be a coordinate process for
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steady bone formation and resorption. Initially, the detailed mechanism of this crosstalk was not
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well understood for years. It was not until 1997 that a molecular bas is for the intercellular crosstalk was discovered in the form of osteoprotegerin (OPG) and its cognate ligand OPG-L. OPG is secreted by osteoblasts, while the OPG-L is expressed on osteoblasts. Both molecules can bind with the receptor activator of NF-κB (RANK) to activate the downstream signal, a typical transmembranous receptor expressed on osteoclast precursors. The binding of OPG-L (also known as RANK-L) on osteoblasts with RANK induces a signaling and gene expression cascade, promoting the formation of osteoclasts from precursors (Ahmed, 2015; Hofbauer, et al., 2000). In
contrast, OPG competes with RANK to bind with RANK-L, which can inhibit osteoclast formation and subsequent bone resorption effectively. 12
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Recently, semaphorins (Sema) have been revealed as key molecules participating in the cell-cell communication between osteoblasts and osteoclasts (Hayashi, et al., 2012). Among the identified semaphorin families, two types are closely related to cell crosstalk. Semaphorin 3A (Sema3A) produced by osteoblasts inhibits osteoclasts, while Semaphorin 4D (Sema4D) secreted by osteoclasts inhibits osteoblasts (Negishi-Koga & Takayanagi, 2012). Other factors are also
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involved in the bone remodeling process. EphrinB2 (Eph2), a membrane-bound molecule located
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on osteoclasts, can bind with ephrinB4 (Eph4) expressed on osteoblast membranes. Remarkably,
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their bindings transduce bidirectional signals. An Eph2/Eph4 binding facilitates the differentiation
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of osteoclasts, whereas a reversed Eph4/Eph2 signaling decreases osteoclastogenesis (Zhao, et al.,
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2006).
Located within lacunae encompassed by highly mineralized bone matrices, osteocytes harbor
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numerous cytoplasmic processes that function through small channels, expediting their
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interconnection with neighboring osteocytes, bone lining cells, and osteoblasts on the bone
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surface. Osteocytes, like osteoblasts, can secret RANK-L or OPG to promote or inhibit osteoclastogenesis, respectively. Also, upon mechanical stimulus, osteocytes secret secondary factors to modify bone physiology. Moreover, nitric oxide (NO), prostaglandin E2 (PGE2), and insulin-like growth factor-1 (IGF-1) can stimulate osteoblast activity, while sclerostin and the dickkopf WNT signaling pathway inhibitor (DKK-1) play a converse role. The extracellular matrix is closely associated with the bone cells and plays an essential role in bone homeostasis. The collagenous matrix generated by osteoblast-progenitors regulate growth
factors (e.g. BMPs), facilitating osteoblast differentiation and matrix maturation (Yang, et al., 2003). Osteoblasts/osteocytes produce matrix metalloproteinases (MMPs) which promote the 13
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remodeling of matrix and development of the lacunocanalicular system. Osteocytes also secrete dentin matrix protein 1 (DMP1) and matrix extracellular phosphoglycoprotein (MEPE) to regulate calcium and phosphate metabolism in matrix (Alford, Kozloff, & Hankenson, 2015). Furthermore, various matrix proteins provide RGD binding sites to bind with integrins on osteoclast, enabling the formation of ruffled border and sealing off of resorptive spaces, where cathepsin K and
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hydrogen ions are then surrounded to degrade type I collagen and demineralize inorganic
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components, respectively (Lakkakorpi, et al., 1991). Along with bone resorbing process,
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osteoclasts regulate extracellular calcium concentration, and in turn, the extracellular and
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intracellular calcium level influence the osteoclast activity (Li, Kong, & Qi, 2006). Apart from
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bone cells, PTH act as a major regulator of the levels of calcium and phosphate in the bone matrix (Wein & Kronenberg, 2018).
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As multipotent stromal cells, MSCs are capable of osteogenic differentiation (Grayson, et al.,
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2015). The bone marrow microenvironment created during bone remodeling directs the fate of
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MSCs. IGF-1 released from the bone matrix can stimulate the differentiation of MSCs to osteoblasts by activating mammalian target of rapamycin (Xian, et al., 2012). Transforming growth factor β (TGF-β), which is released and activated by osteoclasts, can recruit MSCs specifically to local site of repair for new bone formation. The expression of Sema4D on osteoclasts, on the other hand, inhibits MSC differentiation (Crane & Cao, 2014) (Figure 1).
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Figure 1. The interconnection between bone cells and matrix in bone microenvironment.
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Osteoblasts express RANK-L or secret OPG to bind with RANK on osteoclast precursors, which
facilitate or inhibit osteoclast formation, respectively. Sema3A produced by osteoblasts inhibits
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osteoclasts, while Sema4D secreted by osteoclasts inhibits osteoblasts. Eph2, a membrane-bound
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molecule present on osteoclasts, binds with Eph4 expressed on osteoblasts. Eph2/Eph4 binding
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facilitates the differentiation of osteoclasts, when a reversed Eph4/Eph2 signaling decreases osteoclastogenesis. Osteocytes secret RANK-L or OPG to promote or inhibit osteoclastogenesis, respectively. Osteocytes also produce NO, PGE2 and IGF-1 to stimulate osteoblast activity, while release sclerostin and
DKK-1
to
inhibit
osteoblast
activity.
For
matrix
regulation,
osteoblasts/osteocytes produce MMPs to promote the remodeling of matrix and development of the lacunocanalicular system. Cathepsin K and hydrogen ions in ruffled border degrade type I collagen and demineralize inorganic components, respectively. IGF-1 released from the bone
matrix stimulates MSCs differentiation to osteoblasts. TGF-β released by osteoclasts recruits
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MSCs to local site of repair for bone formation while Sema4D inhibit MSC differentiation. More in-depth discussions please refer to the text.
3. Bone-targeting moieties Because of its unique structure and composition, the bone also provides opportunities for
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varieties of agents called bone mineral seekers to selectively target skeletal tissues. Years of
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extensive investigations have demonstrated that different types of moieties, including many small
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molecules (< 1000 Da), as well as large macromolecular proteins, show high bone specificity.
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Typical bone-targeting moieties are classified in Table 2 and will be discussed in detail in the
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following paragraphs.
3.1. Bisphosphonates
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BPs are a class of analogs of naturally occurring pyrophosphates. Fleisch and colleagues first
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reported the biological function of BPs in the 1960s (Mühlbauer, 1968). Since then, BPs have
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been investigated extensively for biomedical applications. These analogs possess a similar ability to regulate bone mineralization as pyrophosphates but are much more chemically stable than pyrophosphates. Structurally, the two phosphonate groups (PO(O−)2) share a common oxygen molecule (P–O–P) in pyrophosphates, but the oxygen molecule in BPs is replaced by a carbon atom (P–C–P). The substitution of the P-C-P backbone in BPs does not affect its affinity for bone minerals but makes it more resistant to most chemical reagents and enzymatic degradation, resulting in an extended residence for BPs in skeletal tissues for up to years (Brown, et al., 2014).
The affinity of BPs for the bone is greatly affected by the molecular structure of BPs. Mechanistically, the P–C–P backbone presents two phosphonate groups to chelate with divalent 16
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interaction with Ca to generate a tridentate binding to HA (Lawson, et al., 2010).
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Based on the presence or absence of nitrogen side groups at the R2 position, BPs can be
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categorized into two groups: nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs
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(non-N-BPs). It has been suggested that the N-BPs possess a higher binding affinity for the bone
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than non-N-BPs (Nancollas, et al., 2006). This difference in affinity could be attributed to the
direct hydrogen bonding action between nitrogen functional groups and the hydroxyl on a HA
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surface. Moreover, N-BPs can significantly inhibit the synthesis of farnesyl pyrophosphate that is
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necessary for osteoclast functioning (Drake, Clarke, & Khosla, 2008). The in vivo bone
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homeostasis will then be shifted toward bone formation due to the reduced osteoclast activity, which does not affect osteoblast bone formation. Non-N-BPs can be metabolized to toxic methylene-containing adenos ine triphosphate (ATP) analog in bone cells, including osteoclasts, inducing substantial cell apoptosis (Reyes, et al., 2016). Besides, the chemical groups positioned at the R1 and R2 chains can be conjugated with nonspecific bone therapeutic agents to obtain osteotropicity (Rotman, et al., 2018). The use of BPs as bone-targeting moieties still faces several potential complications. Because
BPs can inhibit bone resorption, atypical femur fractures (AFF) could be induced by long-term low bone turnover (Dell, et al., 2012). Compared with AFF, osteonecrosis of the jaw (ONJ) occurs 17
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at a much lower level. However, the occurrence rate of ONJ increases when BPs are used under an oncological condition (Khan, et al., 2015). BPs can also cause extra-skeletal adverse effects, including gastrointestinal effects, cancer of the esophagus, and atrial fibrillation (Reyes, et al., 2016). The gastrointestinal side effects could be related to the poor gastrointestinal absorption of oral BP, which prolongs the exposure of gastric and intestinal mucosa to a large amount of BP
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(Pazianas, et al., 2010). In the meantime, taking pills could induce persistent injury of the mucosa,
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which could lead, potentially, to dysplasia of the esophageal cells and increase the risk of cancer
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of the esophagus (Green, et al., 2010). Atrial fibrillation could result from the increased blood
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calcium level, together with the possible inflammation of arterial wall caused by BP (Abrahamsen,
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Eiken, & Brixen, 2009).
The adverse effects of BPs are correlated with the given dosage. At high doses, BPs could
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inhibit bone mineralization and induce osteomalacia. Patients who have never received BP therapy
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and are given a high dose of BP, may experience a typical acute-phase response with fevers up to
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39°C for 1 to 3 days and transient haematological changes. Besides, the fast intravenous injection of BPs at doses of more than 200 to 300 mg could induce severe renal failure (Adami & Zamberlan, 1996).
3.2. Tetracyclines TCs and their analogs are a family of compounds that display a basic chemical structure comprising a tetracyclic naphthacene carboxamide ring system surrounded by various functional groups and substituents. It is well-known that TCs can bind to bone apatite. This special attraction
to skeletal tissues is mainly attributed to the good metal-complexing abilities of TCs, which can chelate with Ca2+ in the HA of bone matrix (Albert & Rees, 1956). Van der Waals interactions and 18
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hydrogen bonding between TCs and HA are also likely to induce surface complexation to bone apatite, contributing to an additional association between TCs and bones (Wang, Hu, & Zhang, 2010). TCs can equally be conjugated with estrone to develop a bone-targeted estrogen (XW-630). Compared to free estrone, TC-estrone seemed to be more efficient in improving trabecular bone connectivity (Lu, Qiu, & Zheng, 1998). Apart from targeting the skeleton, TCs can as well inhibit
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collagenase with a potent anti-collagenolytic effect, that would reduce bone resorption.
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Furthermore, TCs can increase the expression of procollagen mRNA, elevating the number of
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activated osteoblasts (Reichert, et al., 2012). Interestingly, TCs have fluorescent properties and can
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label the surface of a growing bone formation area, which can be used for imaging and
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quantifying new bone formation (Nakamura, et al., 2000).
Doxycycline (DC), a TC analogue, is also osteotropic with a high affinity for mineralized
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bone. Moreover, DC shows potent benefits for connective tissue remodeling and healing. The
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microenvironment of chronic wounds is pro-inflammatory containing a high level of MMP. DC
et al., 2017).
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displays anti-inflammatory and MMP inhib itory effect , thus promoting normal tissue repair (Gomes,
There are several limitations to using TCs. The inherent biological activity involving heartburn, rash, dizziness, hypoglycemia, and nausea is a considerable concern in the practical use of TCs (Valentín, et al., 2009). Moreover, the chelation of TCs to skeletal tissues is permanent, which leads to undesired side effects, especially for teeth discoloration during dental development in children, and this permanent discoloration from yellow or gray to brown depends on the dose of
TCs (Sánchez, Rogers III, & Sheridan, 2004). Additionally, a high dose of TC may induce enamel hypoplasia during calcification (Bevelander, Rolle, & Cohlan, 1961). Despite high osteotropicity, 19
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TCs show decreased affinity for pathologic skeletal sites with low bone turnover, making TCs suboptimal candidates for bone-related diseases, such as osteomyelitis (J. Hatzenbuehler, 2011). Besides, TCs are quite chemically unstable, which further hinders their clinical application. 3.3. Biomimetic bone-targeting moieties Bone-targeting peptides Recently, utilizing the repetitive acidic amino acids of natural bone proteins to interact with
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Ca2+ in mineralized tissues has emerged as a fundamental bone-targeting concept. Among these
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amino acids, acid oligopeptides, composed of repeating aspartic acid (Asp) or glutamic acid (Glu)
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sequences, natively occurring in osteopontin and osteocalcin, show a great affinity for HA
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(Rotman, et al., 2018). Though the exact mechanism is still under debate, the structure of acid
oligopeptides has been demonstrated to correlate to the exclusive interaction between
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oligopeptides and mineralized tissues. Acid oligopeptides with 4 to 10 Asp or Glu units (Asp4-10,
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Glu4-10) are reportedly considered as more biocompatible options for bone-targeting purposes
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(Junko, 2009). The optical isomeric form (L or D) of peptides affects in vivo biocompatibility to some extent. Compared with L-peptides, D-peptides are not readily recognized by the immune system and, thus, promote in vivo biocompatibility (Low & Kopecek, 2012). Oligopeptides’ binding affinity for the bone varies depending on the number of amino acids they contain, the binding rates of small peptides with HA are enhanced with increasing chain lengths of Asp and Glu. However, the binding affinity comes to a steady level when the chain is up to hexapeptides. As a result, acid oligopeptides with over six amino acids in length are the ideal candidates for
binding efficiency requirements. Meanwhile, there is evidence that the chirality of Asp and Glu (L or D) has no impact on mineral chelating properties (Sekido, et al., 2001). 20
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Another oligopeptide, with six repeating sequences of Asp, serine, and serine ((AspSerSer)6), also shows a good skeletal affinity for the bone and has been widely used as a bone-targeting moiety. While Asp8 selectively binds to the bone resorption surface, (AspSerSer)6 displays selective binding to the bone formation surface, as it favorably chelates with osteoblast-mediated mineralizing nodules and amorphous calcium phosphate (Yarbrough, et al., 2010).
f
Apart from oligopeptides, other peptide sequences present osteotropicity. A peptide
oo
consisting of twelve amino acids, VTKHLNQISQSY (VT K), has been confirmed to have a high
pr
affinity for HA and skeleton-like materials. The phosphorylation of serine and the hydroxyl side
e-
group of tyrosine in the VTK peptide sequence are the major interacting domains involved in HA
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binding (William N, 2010).
Bone-targeting proteins
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The most abundant protein in the organic matrix is type I collagen, making it a highly
rn
potential targeting site in bone tissues. Collagen binding domains (CBDs), largely present in the
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collagenolytic proteases of microorganisms, can bind specifically with collagen (Watanabe, 2004). The cDNA of CBDs can be fused easily into the C-terminus or N- terminus of proteins of interest using standard molecular biology techniques. The fusion-protein, with an unimpaired protein structure and bioactivity, can then be obtained by expressing the recombinant protein. The expected proteins, such as PTH and stromal-derived factor-1-alpha (SDF-1α), can acquire the specific binding ability to collagen in the bone (Sun, et al., 2016; Tulasi, 2011). In addition to collagen, several other matrix proteins, including osteocalcin, sialoprotein, and
osteopontin, account for the minor components of the bone matrix. Interestingly, all of these proteins have been demonstrated to have a good affinity for Ca2+ and the mineral surface of the 21
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bone (Ryuichi Fujisawa, 2012). Osteocalcin, a γ-carboxyglutamic acid-containing protein, is the most abundant non-collagenous protein in the bone. It can bind strongly to HA, instead of amorphous calcium phosphate, preventing crystallization. BSP is an acidic glycol-phosphoprotein in the bone that contains RGD (Arg-Gly-Asp) cell-attachment sequences near the C-terminal end; these sequences can be recognized by the presence of integrin αvβ3 and mediate selective
f
attachments to osteoblasts and fibroblasts (Oldberg, Franzen, & Heinegard, 1988). This protein
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also has polyglutamic acid sequences that are responsible for initiating the nucleation of the HA
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crystal (Hunter & Goldberg, 1993). Moreover, BSP shows a unique affinity for collagen, which
e-
further increases the potency for HA nucleation (Baht, Hunter, & Goldberg, 2008). Another
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multifunctional protein, osteopontin, also contains RGD adhesive sequences, as well as Asp-rich
calcium-binding domains, which can bind to the surface of HA effectively. In contrast to BSP’s
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Bone-targeting cells
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nucleation, osteopontin is likely to inhibit the formation and growth of the crystal (Boskey, 1995).
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With pluripotent nature, MSCs can be trafficked to injured tissues, also termed endogenous stem cell homing, and participate in subsequent tissue regeneration (Lin, et al., 2017). In bone tissue, MSCs can be recruited to fractured sites via (SDF)1/CXC chemokine receptor (CXCR) 4 signaling axis and improve healing by increasing the bone formation and bone content of the callus (Kitaori, et al., 2009). As described above, TGF-β released by osteoclasts can facilitate MSC recruitment in bone resorptive sites further. Besides, many integrins, including integrin α1, α2, α3, α4, α5, α6, α11 and β1 are expressed in MSCs (Guan, et al., 2012). Among them, the
overexpression of integrin α4 can promote MSC homing to bone (Mukherjee, et al., 2008).
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Although using biomimetic moieties for bone-targeting presents fewer adverse effects in vivo, their limitations should also be noted. The poor stability of enzymatic cleaving and low oral bioavailability constitute the therapeutic concerns of these moieties in their practical utilization. The manufacturing process is similarly quite complicated, labor-intensive, and requires professional laboratory techniques, resulting in relatively high costs. Moreover, special conditions
f
for transport and storage are required (Aoki, et al., 2012; Sun, 2013).
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3.4. Other moieties
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In addition to the molecules mentioned above, a few other moieties can also be used to target
e-
the bone. The phosphonate groups in BPs are known to play an essential role in their interaction
properties.
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with bone minerals. So, other phosphonate-containing compounds may likewise show similar
Tetraazacyclotetradecane-1,4,8,11-tetramethylene
phosphonic
acid
and
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ethylenediamine tetra(methylene phosphonic acid), both containing four phosphonate groups, can
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chelate to Ca2+ on skeletal tissues (Lange, et al., 2016). Different from BPs, these compounds
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display a negligible physiological effect on bone metabolism (Rotman, et al., 2018). Recently, thanks to the systematic evolution of ligands by exponential enrichment (SELEX), aptamers consisting of short DNA/RNA oligonucleotides can be screened as targeting molecules with strong specificity and affinity. The SELEX method comprises three procedures: selection, partitioning, and amplification. Before selection, a library of oligonucleotides containing 1015 different unique sequences is first synthesized, then incubated with targeted-molecules for selection. After incubation, the unbound sequences are removed using different methods; then the
bound sequences are amplified by PCR and utilized for a new round of selection. Lastly, the specific cell-targeted aptamer candidates are obtained after several cycles (Zhuo, et al., 2017). In 23
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this way, the CH6 aptamer with the inherent merits of high specificity and efficiency that can directly target osteoblasts is selected (Liang, et al., 2015). Radionuclides, such as Strontium and Lanthanides, due to their similar physical and chemical properties to those of calcium, can preferentially be deposited in bone tissues and participate in the metabolic process of bone minerals (Cawthray, et al., 2015).
oo
f
4. Bone-targeting strategies
Targeted therapy has been investigated extens ively for more than thirty years for use in the
pr
treatment of bone-related diseases. The advantages of the unique characteristics of targeted
e-
therapy show that it can improve drug utilization for increased therapeutic outcomes, as well as
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reduce systemic toxicity-related side effects. Generally, bone-targeting strategies can be classified
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4.1. Bone matrix-targeting
al
into two types: bone matrix-targeting and bone cell-targeting strategies.
Thirty-five percent of the dry weight of the bone is organic collagen, and the rest is mainly
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2+
composed of inorganic HA, which contains 99% of the total Ca
in the body. Given their unique
characteristics, both collagen and HA can serve as potential targets of compounds or molecules deposited in bone tissues.
Fusing therapeutic proteins with CBDs is a strategy that is used frequently to target organic collagen in the bone. PTH, an essential protein in regulating bone remodeling, can activate osteoblasts directly. The protein’s functions are mainly mediated by the PTH receptor (PTH1R) that is expressed on osteocytes and osteoblasts (Silva & Bilezikian, 2015). Generally, CBDs consist of amino acids 861–981 of the ColH collagenase of Clostridium histolyticum (Matsushita, 24
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et al., 1998). The fusion proteins of PTH can be synthesized by conjugating the carboxy-terminus of PTH directly with the amino-terminal of CBD (CBD-TH) or with CBD via an adjacent ColH domain known as a polycystic kidney disease domain (PKD, CBD-PKD-PTH). Both hybrid proteins can preferentially bind to type I collagen and increase cyclic Adenos ine monophosphate (cAMP) accumulation in PTH/PTHrP receptor transfected cells, resulting in an anabolic effect.
f
However, in practical use, PTH-CBD showed a 15% increase in bone mineral density (BMD),
oo
while PTH-PKD-CBD induced a modest increase (5%), with the PKD domain potentially
pr
reducing the availability of PTH to the PTH/PTHrP receptor. The results suggested that the direct
e-
link between PTH and CBD is more suitable for the treatment of bone diseases (Tulasi, 2011).
+
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Besides PTH, CBD can also fuse with SDF-1α to selectively bind with collagen, with the resulting +
proteins potentially promoting CD34 and c-kit endogenous stem cells to home in the injured
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region for bone regeneration (Shi, et al., 2016).
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Many compounds and molecules show a specific affinity for HA, demonstrating an excellent
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potential to target bone minerals. Thanks to the development of the chemical conjugating technique, therapeutic agents can be grafted easily with bone-targeting moieties by a linker element to acquire bone affinity. As analogs of natural pyrophosphates, BPs have a strong affinity for calcified tissues and can bind effectively to HA on the bone surface. PGE2 can stimulate bone formation after in vivo systematic administration (Chyun & Raisz, 1984); it can be coupled chemically to BPs via the C-1 carboxyl group or 15-hydroxyl group of PGE2. Besides, more than one equivalent of PGE2 utilizing a polysubstituted BP has been obtained by incorporating two moles of PGE2 per mole of a BP, with the tethered PEG2-BP found to have a good affinity for the bone and to liberate PGE2 at an acceptable rate to stimulate bone growth (Gil, et al., 1999). 25
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However, the PGE2-BP conjugate has not develop a good medication for clinic, as it showed comparable bone formation effect to the parent PGE2 and limited accumulation in localized bone resorptive areas (Ossipov, 2015). Similarly, chemotherapeutic prodrugs have been prepared by conjugating drug molecules (camptothecin) to BPs through an ester-labile linkage to drugs, with a hydroxy group or carbonate-labile linkage binding of the amine functional group of drugs. The
f
prodrugs have shown a satisfactory binding ability to HA on the bone surface and can easily be
oo
activated hydrolytically in physiological conditions (Erez, et al., 2008).
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Apart from BPs, therapeutics can also be linked with other bone targeting moieties. TCs
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show a relatively complex chemical structure and poor stability during chemical conjugation. It is
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possible to separate the HA binding domain from TC by structure-activity relationship study. The tricarbonylmethane group in ring A is sufficient for HA binding (Myers, Tochon-Danguy, &
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Baud, 1983). Estradiol can be conjugated with this functional domain to enhance affinity for HA.
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This bone-targeting system improves the in vivo safety profile of estradiol after administration
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(Neale, et al., 2009). Estradiol can likewise be conjugated with aspartic acid oligopeptide. An estradiol prodrug has been synthesized by linking estradiol at position 3 to L-Asp-hexapeptide via succinate and was used to enhance the expression of the mRNAs of type I collagen α, osteopontin, and BSP, while only increasing BMD with negligible influence on the weights of the uterus and liver (Yokogawa, et al., 2001).
With high drug loading efficacy and small particle size, nanoscale devices are promising transporters of therapeutics to diseased portions of the bone and promote sustained drug release to targeted sites (Liu, et al., 2019). Using variable physicochemical properties, nanoparticles can be functionalized eas ily with bone-targeting ligands to improve the bone affinity of packaged 26
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therapeutics. Poly(lactic-co-glycolic acid) (PLGA) is one of the most commonly used polymers with excellent in vivo biocompatibility and biodegradation and has been approved by the Food And Drug Administration (FDA) for biomedical applications; it is currently used for surgical sutures in the clinic (Lu, et al., 2009). Asp-linked PLGA nanoparticles can be fabricated by conjugating aspartic acid with PLGA nanoparticles directly. These osteotropic nanoparticles show
f
significant HA binding capability. A single Asp residue can serve as a targeting moiety for
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skeletal tissues (Erica J Carbone, et al., 2017). Another way to prepare Asp-functionalized PLGA
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nanoparticles is to synthesize Asp-PEG-PLGA copolymers first and then assemble the copolymers
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into nanoparticles. The use of these nanoparticles in previous in vivo bone affinity assay indicated
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that Asp-PEG-PLGA nanoparticles had higher bone-targeting efficacy than nanoparticles that lack Asp (Fu, et al., 2014). By tagging fluorescein isothiocyanate (FITC) with an Asp peptide,
Besides, PLGA can be grafted to TC via an esterification reaction to form a TC-PLGA
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2014).
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FITC-labeled Asp-PLGA nanoparticles can be prepared further for in vivo imaging (Jiang, et al.,
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copolymer, and the nanoparticles are then fabricated by a solvent emulsification method and display bone-targeting ability, improved curative effects, and reduced adverse effects to other organs (H. Wang, et al., 2015).
Recently, carbon dots (CDs) have attracted much attention for their convenient synthesis, colorful photoluminescence, and good biocompatibility, which have been used extensively for bioimaging, sensing, optoelectronics, catalysis, and energy conversion (J. Zhang & Yu, 2016). Fluorescent CDs for bone imaging can be fabricated using alendronate (ALN) without a nitrogen-doping precursor via a facile hydrothermal method. These ALN-based CDs have a strong
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binding affinity for bone structures and extended skeletal fluorescence-retaining ability post-injection (Lee, et al., 2019).
4.2. Bone cell-targeting Because therapeutic agents are unable to differentiate between concrete cells in bone tissues, therapeutics will act on reachable cells with non-selectivity. Strategies that target specific cell
oo
f
types realize higher therapeutic efficiency and lower side effects, demonstrating great potential both in basic research and clinical application.
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Targeting osteoblasts
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Osteoblasts possess a prominent bone-forming ability and play an essential role in bone
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homeostasis. Osteoblast-specific aptamers can be screened to bind osteoblasts specifically using
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cell-SELEX. In a practical situation, a CH6 aptamer was selected after screening and post-inserted
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into the surface of osteogenic pleckstrin homology domain-containing family O member 1
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(Plekho1) siRNA-encapsulated lipid nanoparticles. The aptamer-functionalized nanoparticles promoted the selective uptake of Plekho1 s iRNA by osteoblasts and osteoblast-specific Plekho1 gene silencing, resulting in enhanced bone formation, improved bone microstructure, and ultimately stimulated bone recovery (Liang, et al., 2015).
Polypeptides have been used widely for targeted delivery owing to their simple spatial structure, small molecular weight, high specificity, strong penetrability, and low immunogenicity. As mentioned above, (AspSerSer)6 has a good affinity for the skeleton and can bind selectively to bone formation surfaces. (AspSerSer)6-attached cationic liposomes can be developed and used to deliver Plekho1 siRNAs to bone-formation surfaces with precision (Zhang, et al., 2012). Besides, 28
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(AspSerSer)6-functionalized nanodevices can be used for selectively transporting Sema3A plasmids to osteoblasts (Yang, et al., 2018).
Phage display is a powerful selection technique for high-throughput screening of peptide or protein interactions. Using a phage or plasmid as the vector, exogenous peptide or protein gene could be fused with a bacteriophage coat protein and expressed on the surface of virion (Wu, et
f
al., 2016). Making use of this tool, Sun et al. ( Sun, et al., 2016) selected a peptide sequence
oo
(Ser-Asp-Ser-Ser-Asp, SDSSD) that showed a binding affinity for osteoblast-specific factor 2 and,
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thus, targeted osteoblasts in a ligand-receptor specific manner. The SDSSD peptide was then
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osteoblast bone formation activity.
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modified on PU nanomicelles to deliver nucleic acids to osteoblasts accurately, promoting
Targeting osteoclasts
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Osteoclasts have an excellent capability of resorbing the mineralized bones to maintain an in
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vivo stable state of the bone. Many factors participate in this process, making them attractive
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targets in osteoclasts. Integrin αvβ3, an adhesion receptor expressed on the surface of osteoclasts, can promote the adhesion of osteoclasts to the bone matrix for subsequent bone resorption activity. Recently, owing to the development of the Protein Chip technology, the inhibition of protein-protein interactions (PPIs) has been considered an emerging approach in disease treatment. IPS-02001, a small molecule inhibiting integrin αVβ3-osteopontin PPI, was screened a few years back using an in silico docking method-integrated ProteoChip technology; and it inhibited the maturation and resorptive activity of osteoclasts by blocking αVβ3 integrin signaling, which reduced ovariectomy-induced bone loss (Park, et al., 2016). Alongside integrin, the microRNAs
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(miRNAs) in osteoclasts also play a critical role in regulating bone homeostasis. It has been demonstrated that elevated miR-214-3p in osteoclasts is closely associated with increased serum exosomal miR-214-3p and reduced bone formation in elderly fractured female and ovariectomized mice. Osteoclast-targeting platforms containing antagomiR-214-3p can be developed by conjugating a D-Asp8 peptide with a cationic liposome. This system inhibited the expression of
f
miR-214-3p, which in turn promoted bone formation in ovariectomized aging mice (Li, et al.,
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2016).
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Targeting osteocytes
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As the most abundant cells in the bone, osteocytes are attractive target sites for their
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important function in bone metabolism. Osteocytes also play a significant role in the crosstalk of osteoclasts and cancer cells. This class of bone cells can manipulate the activity of early cancer
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bone metastasis and subsequent osteoclastogenesis by expressing RANKL, OPG, and sclerostin,
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thereby providing a favorable bone milieu for the settlement of cancer cells (Cui, Evans, & Jiang,
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2016; Zhou, et al., 2015). Therefore, inhibiting osteocyte-mediated osteolysis would suppress the ingrowth and invasiveness of metastatic cancer.
Zoledronic acid (ZA), a third-generation BP, has a high affinity for bone tissues. More importantly, this BP can focus on sites of osteocytes and cancer cells during the early stage of bone metastasis. Additionally, ZA shows a synergistic effect in alleviating metastatic bone destruction alongside traditional Chinese medicine, plumbagin (PL) (Qiao, et al., 2016). A version of an upconversion nanoparticle that contains ZA and PL has also been fabricated, and it specifically targets osteocytes. This system inhibits the phosphorylation of osteocytic protein
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kinase-a, cAMP-response element-binding protein, extracellular regulated protein kinase, and c-Jun N-terminal kinase, in that way decreasing the expression of osteoclastogenic RANKL and sclerostin (Qiao, et al., 2017).
Targeting stem cells
With unlimited self-renewal and excellent differentiating ability into multiple cell types, stem
oo
f
cells have been applied widely in regeneration engineering. Notably, in the aspect of bone injury, MSCs can differentiate into chondrocytes and osteoblasts, contributing to the repair process
pr
(Grayson, et al., 2015). The unique functions of stem cells make them potential targets in the
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bone. Particularly, various surface molecules on stem cells have been identified using large-scale
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analyses, which has paved a way to develop specific affinity reagents for these molecules. Integrin α1, α2, α3, α4, α5, α6, α11, and β1 are expressed on the surfaces of MSCs. Among them, the
al
overexpression of integrin α4 can promote MSCs’ homing to the bone (Mukherjee, et al., 2008).
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Guan et al. (Guan, et al., 2012) synthesized a specific peptidomimetic ligand (LLP2A) against
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integrin α4β1 that had a high affinity for MSCs. By further combining LLP2A with ALN, the resulting compound can facilitate the in vitro migration and osteogenic differentiation of MSCs, as well as in vivo trabecular bone formation. Recently, a DNA aptamer, named Apt19S, was successfully developed using SELEX to target pluripotent stem cells specifically (Hou, et al., 2015). The aptamer was further immobilized on a bilayer scaffold for explic itly recognition and binding with MSCs. After implanting Apt19S into a defective osteochondral area, the aptamer-functionalized scaffold can facilitate the recruitment and binding with MSCs, promoting both the regeneration of defective cartilage and subchondral bone. Moreover, in vivo tests on rats
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have indicated that this kind of scaffold displays excellent performance in the restoration of the osteochondral knee joint (Hu, et al., 2017).
5. Targeted therapy for bone-related diseases
Generally, the coordination between bone-absorbing osteoclasts and bone-forming osteoblasts keeps the bone in a steady state. This equilibrium is disturbed under many pathological
oo
f
conditions of the bone, including osteoporosis, osteosarcoma and bone metastasis, osteoarthritis, bone fracture, and other skeletal disorders. With the development of precision medicine, targeted
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therapy aimed at preselected sites has raised considerable interest in research and achieved much
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progress in bone-related diseases (Figure 2 and Table 3).
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Figure 2. The schematic illustration of targeted therapy for bone-related diseases.
5.1. Osteoporosis
Osteoporosis is a common skeletal disease characterized by remarkably reduced bone mass and strength, as well as impaired skeletal microarchitecture that, in turn, increases the propensity for fragility fractures. As an emerging socioeconomic and medical threat, osteoporosis has a
oo
f
higher prevalence in the aging population, particularly postmenopausal women. A fracture
pr
caused-osteoporosis occurs mainly in the spine, hip, and wrist, which would result in the loss of
e-
mobility and autonomy. The risk of fracture in the lifetime of patients is as high as 40% (Rachner, Khosla, & Hofbauer, 2011). As a consequence, there is an urgent need for the effective prevention
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and therapy of osteoporosis. Generally, the therapeutic strategies for osteoporosis can be classified
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into two categories: the suppression of bone loss and enhancement of bone strength by inhibiting
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the antiresorptive activity of osteoclasts and the acceleration of bone formation and reverse of
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bone deterioration by stimulating osteoblasts.
Salmon calcitonin (sCT), an antiresorptive protein, can produce its antiresorptive effect by acting with calcitonin receptors (CTRs) expressed on osteoclasts (Chambers & Magnus, 1982).
However, sCT has low bone selectivity, given that CTRs are also expressed extensively in many non-skeletal tissues. To overcome this issue, sCT is, therefore, conjugated to thiolated-BP via an SMCC-chemistry to improve site-specificity to the bone. Consequently, the conjugate, with the restored bioactivity of sCT, shows enhanced specificity to mineralized tissues. Regrettably, a conclusive in vivo therapeutic efficacy is missing, meaning that further confirmation is required (Bhandari, et al., 2010). 33
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With satisfactory bio-distribution and tissue-specific properties, nanosystems have been broadly
used
for
targeted
therapy.
Hengst
et
al
(Hengst,
et
al.,
2007)
used
cholesteryl-trioxyethylene-bisphosphonic acid as a targeting moiety and developed the bone-targeted liposomes to treat bone-related diseases, such as osteoporosis, with prolonged exposure to therapeutics and minimized systematic side effects. Ryu et al. (Ryu, et al., 2016)
f
designed a category of ALN conjugated nanodiamonds (ALN-NDs) for potential osteoporosis
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treatment. ALN-NDs can accumulate effectively in the bone after intravenous injection and be
pr
employed potentially for the efficient treatment of osteoporosis thanks to the presence of ALN.
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Estrogen plays a key role in regulating bone metabolism in both females and males (Khosla,
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Amin, & Orwoll, 2008). Supposedly, estrogen therapy can prevent and treat osteoporosis effectively (Khos la & Hofbauer, 2017). However, low selectivity by the skeleton has restricted the
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significant application of estrogen. One classical means to acquire accurate site-specificity to the
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bone is to couple estrogen with bone-targeting moieties. Conjugation with BP, enables estrogen to
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display a preferential profile in the bone, compared to a natural estrogen analog (17β-oestradiol). Therefore, targeted estrogens could potentially improve the compliance of osteoporosis patients by
reducing the medication frequency, as well as adverse effects (Tsushima, et al., 2000). Selective estrogen receptor modulators (SERMs) are derived from estrogen by medicinal chemistry approaches. Commercialized products, such as Raloxifene and Bazedoxifene, are emerging as relatively new classes of drugs for osteoporosis treatment. Interestingly, SERMs have an agonistic effect similar to that of estrogens in tissues, such as the bone, but an antagonistic or neutral outcome in other tissues, like the breast and uterus (Riggs & Hartmann, 2003). From this
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perspective, SERMs themselves already have a targeting property attributed to the different cell responsiveness and their modulation of nuclear receptors instead of spatial targeting (Shang & Brown, 2002).
Unlike antiresorptive therapy, anabolic therapy, another typical modality for osteoporosis treatment, primarily enhances bone formation rather than reduce bone resorption. PTH is a
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representative anabolic drug that has been approved for treating postmenopausal osteoporosis. Despite its better short-term efficacy, compared to BPs, PTH remains only second-line therapy
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due to its considerable side effects (e.g., hypercalcemia) and inconvenient dosing (Neer, et al.,
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2001). There is an indication that hypercalcemia is avoidable, and reduced injection frequency is
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possible if PTH targeting strategies are developed. Generally, this targeted system is constructed by fusing PTH with CBD. Ponnapakkam et al. (Ponnapakkam, et al., 2014) demonstrated that
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PTH-CBD increased spinal BMD by 14.2% after 5 months without inducing hypercalcemia
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following monthly injections in ovariectomized rats. PTH-CBD also increased the level of ALP in
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serum, which is consistent with its anabolic effect. Even for a single subcutaneous administration, PTH-CBD showed a sustained bone anabolic effect for an extended period (9–12 months) with no
hypercalcemia (Ponnapakkam, et al., 2012).
PTH aside, the prostaglandin hormone, PGE2, shows an anabolic activity as well and can stimulate in vivo bone growth (Jee, Ke, & Li, 1991). Four receptor subtypes (EP1, 2, 3, and 4) interact with PGE2. Of the four receptor subtypes, EP4 plays a crucial role in the bone-forming
activity of PGE2. There is evidence that activating the EP4 receptor can suppress the apoptosis of osteoblasts and osteoid precursor cells in bone marrow (Machwate, et al., 2001). However, both 35
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PGE2 and EP4 agonists have several side effects, including gastrointestinal disturbance and vasodilation. To avoid drawbacks and realize a sustained and concentrated impact in the bone, the EP4
receptor
agonist
is
conjugated
with
alendronic
acid
via
a
cleavable
dipeptide-para-aminobenzyl alcohol linker. This prodrug has synergistic bone-forming effects through the EP4a and inhibition of resorption by alendronic acid, possessing a significant potential
oo
f
to treat osteoporosis (Xie, Chen, & Young, 2017).
Stem cell therapy could potentially reduce the susceptibility of fracture and increase mineral
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density by differentiating into osteoblasts, which would be promising for the treatment of
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osteoporosis (Antebi, Pelled, & Gazit, 2014). Allogeneic MSCs isolated from the bone marrow
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have been infused systematically into mice with dexamethasone-induced osteoporosis in the past, with the transfused MSCs homing and inhabiting in the recipient bone marrow for more than 4
(Sui, et al., 2016). Gene engineering is usually used for MSC modification to
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osteoblastogenesis
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weeks. These donor cells committed to Osterix (Osx)+ osteoblast progenitors and induced
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enhance its functionality for tissue regeneration. Li and coworkers (Li, et al., 2016) constructed baculovirus-engineered MSCs expressing miR-140* or miR-214 sponges. These hybrid vectors
transfected MSCs continuously attenuated the cellular levels of miR-140*/miR-214, promoting osteogenesis and repressing osteoclast maturation in vitro. Compared with miR-140*, reducing miR-214 displayed more potent effects. In an osteoporotic rat model, the allotransplantation of miR-214 sponges-expressing MSCs promoted bone healing, remodeling and bone quality (BMD, trabecular thickness, trabecular numbers, and trabecular distance) after 4 weeks.
5.2. Osteosarcoma and bone metastasis 36
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A malignant bone tumor is a highly aggressive tumor that induces destructive changes in the bone structure and causes severe bone pain and other skeletal events. Generally, aggressive bone tumors are classified into primary malignancies (e.g., osteosarcoma) and adaptive bone metastases from other malignant tumors. Osteosarcoma
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Osteosarcoma, the most common type of primary sarcoma in the bone, is characterized by the
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presence of stromal cells that can generate bone-like tissues (Abarrategi, et al., 2016). Standard
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chemotherapy is used customarily as a first-line treatment and has improved the long-term overall
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survival of patients. However, owing to the rigidity, low blood flow, and reduced permeability of
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skeletal tissues, a high dose of chemotherapeutic agents that would cause considerable toxicity is
required (Li, et al., 2016). A more efficient approach is to develop bone-targeted strategies.
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Kopecek and co-workers (Low, Yang, & Kopecek, 2014) utilized D-ASP octapeptide and
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doxorubicin (DOX) to create bone-targeted micelles as potential osteosarcoma therapeutics. The
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micelles displayed rapid adsorption toward HA and potential cytotoxicity to osteosarcoma Saos-2 cells. Integrin avβ3 and avβ5 are expressed widely in osteosarcoma cells. RGD, a cell affinitive peptide, can interact with these integrins and, thus, be used for targeting osteosarcoma. On this basis, Fang et al. (Fang, et al., 2017) developed RGD-decorated biodegradable polymeric micelles loaded with DOX and used them to target MG63 osteosarcoma cells specifically, which resulted in higher cytotoxicity than that obtained with the use of their non-targeted counterparts. Folate receptors are also overexpressed on the surface of osteosarcoma cells. Liposome-packaging
antineoplastic agents (curcumin and C6 ceramide) were modified with folic acid in another
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research to bind with folate receptors, and the targeting liposomes displayed enhanced cell cytotoxicity in osteosarcoma-ridden cells (Dhule, et al., 2014). Osteosarcoma often occurs in the distal femur, proximal humerus, and proximal tibia, all areas with abundant blood supply. This bone tumor depends on the development of new blood vessels, in a process known as angiogenesis, for growth and metastasis (Xie, Ji, & Guo, 2017).
f
Vascular endothelial growth factor (VEGF) is a key tumor-derived angiogenic factor that can
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stimulate angiogenesis while increasing vascular permeability, facilitating tumor progress (Quan
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& Choong, 2006). Besides, the VEGF level correlates with poor prognosis in osteosarcoma
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patients (DuBois & Demetri, 2007). Thanks to the advancement in biotechnology though, VEGF
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receptor tyrosine kinase inhibitors (TKIs), the most typical anti-angiogenesis targeting therapy,
have been developed successfully and used to treat sarcoma in the clinic. Although T KIs have not
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been applied in clinical osteosarcoma, clinical trials have shown promising outcomes. The Italian
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Sarcoma Group conducted a phase II trial using sorafenib to treat relapsed and unresectable
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osteosarcoma and showed that TKI-targeting therapy increased the 4-month progression-free survival from < 30-46% (Grignani, et al., 2012). There is evidence that several VEGF subtypes are involved in the VEGF family, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and VEGF-F (Niu & Chen, 2010). Among them, the pathway mediated by VEGF-A and VEGF receptors plays a vital role in the pro-angiogenic function of tumors and is prioritized for developing anti-angiogenic therapy. Liang et al (Liang, et al., 2017) utilized CRISPR/Cas9, a powerful genome editing technology, to
generate CRISPR/Cas9 plasmids encoding VEGF-A gRNA. The researchers then screened a cell-specific aptamer (LC09) to improve tumor-targeted characteristics and subsequently 38
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fabricated an LC09-functionalized PEG-PEI-Cholesterol lipopolymer encapsulating CRISPR/Cas9 plasmids for anti-angiogenesis therapy. This system decreased the expression and secretion of VEGF-A, as well as angiogenes is by effective VEGF-A genome editing in osteosarcoma, inhibiting both primary tumor and lung metastasis. miRNA-based therapy has emerged as an attractive strategy in osteosarcoma treatment
f
because of the critical role of miRNA in tumorigenesis and growth. Reportedly, upregulating
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miR-132 can inhibit the proliferation of osteosarcoma cells by arresting the cell cycle at the G1/S
pr
phase, which is mediated by reducing cyclin E1 expression (Wang, et al., 2014). Besides,
e-
miR-133a possesses an antitumor effect by decreasing the proliferation and promoting the
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apoptosis of osteosarcoma cells, a role probably attributed to the suppressed expression of B-cell
lymphoma-extra large (Bcl-xL) and myeloid cell leukemia-1 (Mcl-1) (Ji, et al., 2013). In a recent
al
study, the loss of miR-34a, miR-93, and miR-200c was revealed to occur during tumor switch
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from avascular dormancy to the fast-growing angiogenic phenotype. Subsequently, dendritic
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polyglycerol nanopolyplexes were designed to package these miRNAs for targeting osteosarcoma. After reconstituting the miRNAs into osteosarcoma cells using nanopolyplexes, they were found to reduce angiogenetic factors and cell migration, including their target gene levels, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, thereby prolonging the dormancy period of progressive osteosarcomas (Tiram, et al., 2016). Given that osteosarcoma cells possess osteoblastic features, targeting osteoclast functions could be a potentially useful approach to treat osteosarcoma (Zhou, et al., 2014). ZOL, a member
of BPs, has shown a good affinity for bone tissue. Moreover, ZOL can reduce tumor-induced osteolysis by inhibiting osteoclasts directly and attenuating the expression of RANKL and 39
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monocyte chemoattractant protein-1. These potential outcomes are in line with the significant suppression of in vivo tumor growth (Ohba, et al., 2014). With the advancement in gene engineering, it is convenient to engineer T cells genetically with tumor-associated antigens for immunotherapy. The human epidermal growth factor receptor (HER2) is a kind of oncogene expressed in around 60% of primary osteosarcoma. Ahmed and
f
colleagues’ (Ahmed, et al., 2009) adoptive transfusion of HER2-specific T cells induced
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regression of established osteosarcoma xenografts and increased the overall survival of
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tumor-bearing mice. In a follow-up study, the HER-2-specifc CAR T cells targeted drug resistant
e-
tumor-init iating cells (TICs) and remarkably reduce TICs in bulk tu mors (Rainusso, et al., 2012).
Pr
However, during the pathogenesis, progression and metastasis of osteosarcoma, there is a high
incidence of alterations in genetic information, causing tumor heterogeneity and therapeutic
al
obstacles (Wang, et al., 1998). Identifying and targeting mutated genes in osteosarcoma could
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boost the efficiency of cancer treatment. TP53 gene is a common mutant tumor suppressor gene in
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osteosarcoma and its mutation would lead to the loss of the tumor suppressor function of wild-type TP53 (Duffy, Synnott, & Crown, 2017). Tang et al. (Tang, et al., 2019) used a CRISPR-Cas9 system and a TP53 inhibitor (NSC59984) to knock-out mutant TP53 in osteosarcoma cells with specificity. Following the inhibition of mutant TP53, the migration, pro liferat ion, and tumor formation activity of osteosarcoma cells decreased efficiently. Moreover, the knockout of mutant TP53 reduced the level of oncogene (IGF-1R), anti-apoptotic proteins (Bcl-2), and Survivin in osteosarcoma cells.
Bone metastasis
Bone metastasis, which occurs in 70 % to 80 % of patients, is common in patients with aggressive cancer, especially prostate and breast cancers (Coleman, 2006). In the skeleton, 40
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multi-step processes are involved in metastasis development. Tumor cells need to disseminate from the primary site, colonize and survive in the new microenvironment, escape from dormancy to proliferation state, and eventually grow uncontrollably (Croucher, McDonald, & Martin, 2016). Tumor metastasis in the bone would cause unbearable pain, pathologic fracture, spinal cord compression, and hypercalcemia, significantly reducing the quality of life of patients (Pentyala, et
f
al., 2000). With the advancement in precision medicine, new approaches and therapies have been
oo
developed to alter the course of bone metastasis. In a real-world setting with the use of
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bone-targeted denosumab among patients with metastatic tumors, greater compliance and longer
e-
persistence were observed, indicating that targeted therapy may improve treatment efficacy,
Pr
meaning that it holds significant potential for the treatment of bone metastasis (Qian, Bhowmik,
Kachru, & Hernandez, 2017).
al
Prostate cancer is one of the most common malignancies and ranks as the second leading
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cause of cancer-related deaths in men (Siegel, Miller, & Jemal, 2019). What is worse, almost 80%
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of patients develop aggressive bone metastasis, substantially reducing expected overall survival to less than 1 year (Cheville, et al., 2002). Unlike other cancer types, the initial metastasis of prostate cancer is limited to the skeleton that is often the only spread site in the late stage. Targeted therapy is promising in the way it controls bone metastasis owing to its unique characteristic of focusing on a given area. As the most abundant component in the bone, the bone matrix also contributes to initiation and support of cancer metastasis in the bone. Converting the bone matrix to a less favorable environment for metastatic tumor cells could be a potentially rewarding treatment
strategy.
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The systemic administration of radiopharmaceuticals has a long history of alleviating bone metastasis. The FDA has approved Strontium-89 (Porter, et al., 1993) and samarium-153 (Sartor, et al., 2004) for commercialized use in treating metastatic prostate cancer, and these substances have shown preferential uptake in areas with high bone turnover, such as metastatic lesions, resulting in improved clinical outcomes in patients with bone metastasis. Besides, rhenium-186, Sr, and rhenium-188 all show a satisfactory effect on palliating bone metastasis in clinical trials.
f
89
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Another radiopharmaceutical radium-223 exhibits delayed symptomatic skeletal events, improved
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pain control, favorable toxicity profile, and a remarkable overall survival benefit in men with
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metastatic prostate cancer (Blacksburg, Witten, & Haas, 2015). In a phase II study of patients with
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hormone-refractory prostate cancer and bone pain, radium-223 treatment prolonged the median
time of prostate-specific-antigen progression to 26 weeks compared to 8 weeks for placebo.
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Moreover, the median overall survival was 65.3 weeks for radium-223-treated patients while that
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for the placebo group was shorten to 46.4 weeks (Nilsson, et al., 2007).
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The metastasis of prostate cancer to the bone is more likely to be osteoblastic instead of lytic, indicating that inhibiting the increased bone deposition by osteoblasts could be an appealing therapeutic option. Endothelin-1 (ET-1), a potent vasoconstrictor, can stimulate osteoblasts into phenotypes of osteoblastic bone lesions in metastatic prostate cancer (Nelson, et al., 1995). Based on these findings, antagonizing ET-1 is considered a promising therapy. In 2018, a phase III clinical trial (SWOG S0421) introduced a strategy combining chemotherapeutic docetaxel with an ET-1 antagonist (Atrasentan) to treat metastatic castration-resistant prostate cancer. Though no
significant difference was found, the therapy with Atrasentan showed 44.0% pain palliation and
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28.7% functional status compared to 41.7% and 24.2% in the control group, respectively (Unger, et al., 2017). According to the microscopic analysis of skeletal metastatic foci, bone resorption mediated by osteoclasts could prime the bone for osteoblastic metastasis. Hence, targeting osteoclasts could serve as an alternative approach to control metastasis development. BPs, with a high affinity for
f
the skeleton and an excellent ability to inhibit osteoclast activity, have been used in metastatic
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cancer treatment. Notably, zoledronate has been approved for treating bone metastases of prostate
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cancer in the clinic. Because the RANK/RANKL/OPG signaling pathway is essential for
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osteoclast-mediated bone resorption, using OPG-Fc containing an OPG binding domain could
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block the RANK pathway from activating osteoclasts, suppressing the growth of metastatic
tumors (Yonou, et al., 2003).
al
Breast cancer, which is the most common cancer type in women, invades distant organs
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preferentially, especially the bone. Killing tumor cells in the bone directly is an effective way of
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treating metastatic cancer. Cytotoxic chemotherapeutics can cause cytotoxicity to tumor cells and attenuate metastatic tumor progress. However, low selectivity and high dose-related toxicity have
restricted the therapeutic efficacy of these drugs significantly. Reportedly, nanotechnology and bone targeting moieties could help resolve this dilemma to some extent. Zhou et al. (Zhao, et al., 2019) used Glu6 -RGD as a targeting ligand to fabricate liposomes loaded with paclitaxel, which showed extraordinary targeting activity on metastatic cancer cells, inducing higher cytotoxicity. Similarly, Liu’s group (Zhu, et al., 2018) developed a class of ALN-functionalized micelles encapsulating bortezomib-catechol conjugates, and this prodrug showed an acid-responsive drug
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release performance and minimized systematic toxicity. Moreover, this targeted platform remarkably suppressed the growth of cancer cells at metastatic bone lesions and decreased the destruction of the metastatic bone structure.
As described above, osteoclasts play an essential role in bone metastasis from primary tumors. A therapeutic modality simultaneously working on bone resorption and tumor growth
oo
f
could be a meaningful strategy to treat breast cancer-related bone metastasis. ALN-modified polymer nanoparticles have been fabricated to package cisplatin prodrugs to treat bone metastasis
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originating from breast cancer. This platform not only inhibited tumor growth in the bone
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effectively but also decreased osteoclastic bone destruction efficiently (He, et al., 2017).
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ALN-functionalized nanoparticles have similarly been developed to load DOX and have shown suppressed tumor growth and reduced bone resorption with negligible systematic toxicity (Zhao,
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5.3. Osteoarthritis
rn
al
et al., 2017).
Osteoarthritis is a degenerative and heterogeneous joint disease that can cause pain, stiffness, and even disability to patients. Specifically, this “joint disorder” is characterized by articular
cartilage degradation, subchondral bone sclerosis, osteophyte formation, and synovial inflammation (Herrero-Beaumont & Roman-Blas, 2013). Several targeted approaches have been explored in osteoarthritis treatment based on the development and features of osteoarthritis.
Increasing evidence shows that subchondral bone remodeling hightens during the progression of osteoarthritis (Bellido, et al., 2010; Goldring & Goldring, 2010), and this subchondral bone 44
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resorption usually occurs in the early phase of osteoarthritis development. Hence, inhibiting osteoclastic bone resorption could be a potentially useful therapeutic option. With a critical role in bone turnover, BPs can serve as both targeting moieties and efficient therapeutic agents, providing benefits
for
osteoarthritis
treatment.
Moreau
and
colleagues
found
that
tiludronate
(TLN) treatment resulted in less joint effusion, reduced level of PGE2 in synovial fluids, and
f
larger subchondral bone surfaces when compared with placebo controls. TLN also decreased
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inflammatory factors, including matrix MMP-13 and ADAMTS5 in cartilage and cathepsin K in
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the subchondral bone, further alleviating the symptoms of osteoarthritis (Mor eau, et al., 2011).
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Alongside preclinical investigations, BPs display promising outcomes in clinical application.
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According to annually collected patient data from the NIH Osteoarthritis Initiative cohort over 4
years, BP users had lesser joint space narrowing over time (Laslett, et al., 2014).
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Repetitive mechanical injury is a vital signal for the occurrence and progression of
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osteoarthritis. Chondrocytes are generally accepted as the target of these abnormal biomechanical
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factors, making them ideal targets for osteoarthritis treatment (Goldring, 2000). Pi et al. (Pi, et al., 2011) identified a chondrocyte-homing peptide (CAP, DWRVIIPPRPSA) with a two-step
biopanning using synovium and cartilage explants from healthy rabbits and conjugated this CAP covalently with polyethylenimine (PEI) to construct a non-viral vector. The PEI-CAP copolymers were then used to condense siRNA in nanoparticles to silence hypoxia-inducible factor-2α, a key factor in chondrocyte catabolic state. The cartilage-targeting nanoparticles downregulated catabolic
factors in vitro, maintained cartilage integrity, and alleviated synovium inflammation in vivo (Pi, et al., 2015).
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NF-κB signaling pathways are involved extensively in inflammatory diseases and play an essential role in subchondral bone resorption. Notably, synoviocytes and chondrocytes secrete pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), which trigger osteoblasts to release RANKL to bind with RANK. NF-κB transcription factors are then activated for subsequent bone resorptive activity (Rigoglou, Papavassiliou, & biology, 2013). Therefore, targeted therapies
f
inhibiting NF-κB pathways could be acceptable approaches to treat osteoarthritis. In a
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staphylococcus aureus-induced osteoarthritis model, combinational therapies, composed of
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antibiotics with RANK-Fc or OPG-Fc, reduced the expression of bone resorption makers,
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including osteocalcin, the C-terminal telopeptide of type I collagen, and TRACP5b, mitigating
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cartilage/bone destruction (Verdrengh et al., 2010). To block the NF-kB signaling pathway further
and accurately, Doschak et al. (Doschak et al., 2009) conjugated OPG with BP chemically, and
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after systemic administration, OPG-BP conjugates accumulated highly in the bone, suggesting that
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they could, potentially, be applicable in the treatment of osteoarthritis with active bone
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remodeling.
5.4. Bone fracture
Bone fractures pose major challenges to orthopedic practice. Around 5-10% of fractures result in delayed healing o r non-union (Novicoff, et al., 2008). Despite the fact that autologous bone graft is regarded as a gold-standard treatment in fracture non-union, their application can lead to donor site morbidity (Kneser, et al., 2006). Alternatively, recombinant human bone morphogenetic protein (rhBMP)-2 and rhBMP-7 are used for bone harvesting. However,
rhBMP treatments have a very narrow indication and require megadoses of the protein (Virk 46
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& Lieberman, 2012). With the latest signs of progress made in cell and molecular biology, more
effective modalities are developed to restore the structural integrity of bone.
As previously mentioned, MSCs can traffic to injured tissues and differentiate into the osteoblasts and chondrocytes for bone healing. Therefore, MSC-based cell therapy could serve as a potential strategy in fracture repair. Reportedly, the concentration and counts of injected MSCs
oo
f
are in proportion to the healing rate. A practical investigation showed that the fracture of patients who received less than 1000 MSCs per mL and total 30,000 MSCs did not heal, whereas those of
e-
pr
patients given 1500 MSCs per mL and total 54,000 MSCs healed (Gomez-Barrena, et al., 2015).
Although MSCs have extraordinary performance in tissue engineering, their differentiation
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and homing ability remain limited for efficient bone regeneration. To improve this condition, Xu
al
et al. (Xu, et al., 2015) developed Sry-related high-mobility group box 11 (Sox11)-modified
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MSCs by transducing lentivirus carrying Sox11 into MSCs for fracture healing. The results
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demonstrated that the overexpression of Sox11 enhanced the BMP/Smad signaling pathway and activated the promoter activity of Run x2 and CXCR4. Co mpared with control MSCs, more So x11-overexpressed MSCs migrated to the fracture area, initiated callus ossification, and promoted fracture healing in an open femur fracture model. Salvianic acid A (SAA) is a water-soluble active
compound extracted from salvia miltiorrhizae (Danshen), which has potent anabolic ability (Cui, et al., 2009). However, the clinical translation of SAA is greatly impeded by its short half-life in serum and its lack of osteotropicity. To deal with these conditions, Liu et al. (Liu, et al., 2018)
develop a bone-targeting liposome formulation to deliver SAA specifically to the bone. The author synthesized pyrophosphorylated cholesterol by conjugating pyrophosphate to cholesterol via a 47
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triethylene glycol linker and used it as the targeting ligand. The SAA-loaded liposomes were then
prepared using a reverse-phase evaporation method with pyrophosphorylated cholesterol and lecithin as the backbone. The targeted-liposome formulation showed a high affinity for HA in vitro and robust ability of bone-targeting and long retention in vivo. In a delayed femur fracture union mouse model, SAA-loaded targeting liposome was found to shorten healing time
f
remarkably (from > 64 days to 42 days), improve histologic and histomorphometric parameters
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and mechanical property outcomes.
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5.5. Other bone-related diseases
Apart from the skeletal maladies mentioned above, several other bone-related conditions also
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benefit from targeted therapy. PDB is a common skeletal disorder with increased and inordinate
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bone remodeling, leading to osteolytic and osteosclerotic lesions (Vallet & Ralston, 2016). BP is
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one of the first-line medications for treating PDB because of its extraordinary inhibitory effects on
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bone turnover and innate bone affinity. Reportedly, the RANKL/OPG ratio in serum lessened after BP treatment, decreasing subsequent bone resorption and attaining highly efficient PDB therapy (Martini, et al., 2007).
Corticosteroids are routinely used to treat inflammatory and autoimmune diseases but their use is limited by steroid-associated osteonecrosis (SAON), a severe complication that often induces subchondral bone destruction (Chan, et al., 2006). Chen et al. (Chen, et al., 2018) developed a class of Asp8-functionalized liposomes loaded with a small phytomolecule (icaritin) for SAON prevention and found that liposomes alleviated steroids-treated rats of SAON
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efficiently, with remarkably decreased osteocyte apoptosis, as well as increased osteoclastogenesis and osteogenesis.
Osteomyelitis is an inflammatory disease accompanied by severe bone destruction (Lew & Waldvogel, 2004). Current therapy for osteomyelitis focuses mainly on antimicrobial issues. However, even therapeutic efficiency in these instances is usually restricted by the limited
oo
f
concentrations of antibiotics that reach the bone. Promisingly, Sedghizadeh and coworkers have established an osteoadsorptive BP-ciprofloxac in conjugate that demonstrates a significantly
pr
improved therapeutic index in osteomyelitis treatment compared to ciprofloxacin (Xie, et al.,
6. Conclusion and perspectives
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e-
2017).
al
In this review, we summarized the recent progress in bone-targeted therapy. Targeted therapy
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for bone-related diseases has several advantages over standard treatment procedures. Therapeutic
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agents are concentrated in the targeted skeleton to a maximum extent, decreasing the required dosage significantly, and promoting the therapeutic efficacy of the agents. Additionally, the retention time of the drugs is prolonged in the targeted area with improved bioavailability.
Furthermore, the systematic toxicities of these agents are substantially reduced in the controlled non-specific and unintended distribution to other tissues. We also presented the composition of skeletal tissues, including the extracellular matrix and cells, in detail. With the understanding of bone biology, we next summarized the commonly used bone-targeting moieties, with emphasis on BPs, TCs, and biomimetic proteins and peptides, as well as targeting strategies in the bone. Lastly,
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we discussed the potential application of targeted therapy in the treatment of bone-related diseases. It appears that a targeting strategy is a promising approach to skeletal disease treatment.
Though the existing targeted therapy has so far been a hugely promising success, there are still considerable obstacles that hinder its practical application. Unlike other soft tissues, the bone is characterized by its rigidity, low permeability, and reduced blood flow, features that limit the
oo
f
reach of most of the current targeting moieties, such as receptors and biomolecules, to the bone. However, bits of existing targeting moieties that do reach the bone are slowly or even hardly
pr
cleared from the body, which would cause long-term safety concerns. Moreover, most of the
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targeted therapies are still at laboratory phases of investigations, and researchers are finding it
Pr
challenging to advance them to the clinical stage. Therefore, more researches need to be made to resolve the dilemma faced in the use of bone-targeted therapy. With a comprehensive
al
understanding of bone biology and the rapid development of biotechnology, it is possible to
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explore more effective moieties to target the skeleton in the future. Potential options are now in
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the numbers, meaning that the suboptimal targeting moieties could be substituted by safer ones. Furthermore, clinical translations could be accelerated using advanced development in genomics,
genetics, and cell biology. Exploiting effective models to minimize the physiological differences between animals and humans may also shorten the period between the basic research and clinical application. Nevertheless, targeted therapy has various merits, exhibits satisfactory benefits, and could be an appealing strategy in bone-related disease treatments.
Conflicts of interest The authors declare that there is no conflict of interest. 50
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Acknowledgements This work was supported financially by the National Natural Science Foundation of China [Grant
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Pr
e-
pr
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f
number: #81672216, #81874026]
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Table 1. Summary of bone cells
Cell type
Osteoblasts
Resources
MSC lineage
Ref
Cuboidal shaped cells with plenty of rough endoplasmic reticula, well-developed Golgi apparatus, and diversified secretory vesicles
Bone-forming abilities through the deposition of the organic matrix and participation in subsequent bone mineralization
f o
(Marks & Popoff, 1988; Florencio-Silva, et al., 2015; Burr, 2019; Yadav, et al., 2016)
Reacquire secretory abilities; Prevent direct contact between bone matrixes and osteoclasts and participate in osteoclast differentiation
(Matic, et al., 2016; Miller, et al., 1989; Hienz, Paliwal, & Ivanovski, 2015)
Resorb fully mineralized bones
(Detsch & Boccaccini, 2015; Teitelbaum, 2000; Merolli, et al., 2018)
Permit the diffusion of mineral and fluids; Detect mechanical pressures; Regulate osteoblasts and osteoclasts
(Sommerfeldt & Rubin, 2001; Shea & Miller, 2005; Rochefort, Pallu, & Benhamou, 2010; Mori & Burr, 1993; Prideaux, Findlay, & Atkins, 2016)
l a n
Osteoblasts
o r p
e
r P
r u o
Hematopoietic stem cell lineage
J Osteocytes
Functions
Flat-shaped cell with extremely flat nuclei and few cytoplasmic organelles
Bone lining cells Inactive osteoblasts
Osteoclasts
Structure
Polarized and multinucleated giant cells
A dendritic morphology with a higher number of filopodia
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Table 2. Summary of bone-targeting moieties
Classifications
BPs
Targeting moieties
Targeting site
BPs
TCs
Biomimetic bone-targeting moieties
Acid oligopeptides composed of repeating Asp or Glu
J
HA
References
Induce atypical femur fractures; Osteonecrosis of the jaw; Target HA surface; Shift bone Gastrointestinal effects; Cancer of homeostasis toward bone esophagus and atrial fibrillation; formation; Induce osteoclast Inhibit bone mineralization and apoptosis induce osteomalacia, typical acute-phase response and renal failure at high dose
(Yewle, 2012; Lawson, et al., 2010; Drake, Clarke, & Khosla, 2008; Dell, et al., 2012; Khan, et al., 2015; Adami & Zamberlan, 1996)
Target skeletal tissues; Have broad spectrum antibiotic activity; Reduce bone resorption; Label the surface of growing bone formation area
Cause inherent biological activity including heartburn, rash, dizziness, hypoglycemia and nausea; Stain teeth in dental developing children; Being chemical unstable; Induce enamel hypoplasia during calcification at a high dose
(Albert & Rees, 1956; Reichert, et al., 2012; Nakamura, et al., 2000; Valentín, et al., 2009; Bevelander, Rolle, & Cohlan, 1961)
Have good affinity toward HA
Poorly stable to enzymatic cleavage; Low oral bioavailability; Complicated production process;
(Yarbrough, et al., 2010; William N, 2010; Tulasi, 2011,
al
o r p
e
r P
rn
u o
HA
limitations
f o
HA
TCs
Bioactivities
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(AspSerSer)6
VTK
HA
CBD
Collagen
Produce targeting
Osteocalcin
HA
Bind to HA; Prevent the growth of crystal
BSP
Osteoblasts, fibroblasts, collagen
Target osteoblasts, fibroblasts and collagen; Initiate the nucleation of HA crystal
Osteopontin
HA
MSCs
Injured bone
l a n
r u o
J
Other moieties
Chelate with osteoblast-mediated mineralizing nodules and amorphous calcium phosphate Target HA and skeleton-like materials
Bone formation surface
fusion-protein
Harsh conditions for transport and storage
f o
for
Ryuichi Fujisawa, 2012; Hunter & Goldberg, 1993; Boskey, 1995; Aoki, et al., 2012; Kitaori, et al., 2009)
o r p
e
r P
Bind to the surface of HA; Inhibit the formation and growth of crystal Home to fractured sites in bone 2+
HA
Chelate with Ca on skeletal tissues; No effect on bone metabolism
Long-term safety concerns
(Lange, et al., 2016)
CH6 aptamer
Osteoblasts
Target osteoblasts
High cost; Complicated production process
(Liang, et al., 2015)
Radionuclides
HA
Deposit in bone and partic ipate in metabolic process of bone Long-term safety concerns minerals
Phosphonate-containing compounds
54
(Cawthray, et al., 2015)
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Table 3. A brief summary of targeted therapy for bone-related diseases
Bone diseases
Osteoporosis
Osteosarcoma
Bone metastasis
Therapeutics
Targets
Effect
Reference (Ryu, et al., 2016) (Riggs & Hartmann, 2003) (Ponnapakkam, et al., 2012) (Xie, Chen, & Young, 2017)
ALN-NDs
Osteoclasts
Accumulate in bone and possess potential to treat osteoporosis
SERMs
Osteoclasts
Targeted therapy for osteoporosis
PTH-CBD
Osteoblasts
Has high bone affinity and sustained
Alendronic acid-conjugated EP4 receptor agonist
Osteoblasts
Bone-targeting and synergistic bone forming effects
RGD-decorated micelles
Osteosarcoma cells
Induce higher cytotoxicity to tumor cells
Injured bone
Promoted bone healing, remodeling and bone quality (BMD, trabecular thickness, trabecular numbers, and trabecular distance)
(Li, et al., 2016)
Decrease VEGF expression and inhibiting tumor growth
(Liang, et al., 2017)
Reduce factors for angiogenesis and cell migration
(Tiram, et al., 2016)
Baculovirus-engineered MSCs LC09 aptamer-functionalized lipopolymers MicroRNAs-packaged nanopolyplexes Mutant TP53 knockout CRISPR-Cas9 system ZOL
l a n
J
r u o VEGF
ro
miRNA in osteosarcoma Mutant TP53
Osteoclasts
Radium-223
Bone matrix
OPG-Fc
Osteoclasts
f o
p e
anabolic effect
r P
Inhibit the migration, proliferation, and tumor formation activity of osteosarcoma cells Reduce tumor-induced osteolysis Improve the symptomatic skeletal events and pain control as well as reducing toxicity Block RANK pathway and inhibit metastatic tumor 55
(Fang, et al., 2017)
(Tang, et al., 2019)
(Ohba, et al., 2014) (Blacksburg, Witten, & Haas, 2015) (Yonou, et al., 2003)
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Glu6-RGD-decorated liposomes ALN-modified nanoparticles
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Tiludronate Osteoarthritis
Metastatic cancer Induce higher cytotoxicity cells Inhibit tumor growth and decrease osteoclastic bone Osteoclasts destruction Subchondral Decrease inflammatory factors and alleviate the symptom of bone osteoarthritis Silence HiF-2α; Downregulate catabolic factors, maintain Chondrocytes cartilage integrity and alleviate synovium inflammation Block RANK/RANKL pathway and induce active bone NF-κB remodeling for osteoarthritis treatment Migrate to the fracture area, initiate callus ossification and Fracture area promote fracture healing Show high affinity for HA; Shorten healing time; Improve Bone matrix therapeutic outcomes
CAP-PEI based nanoparticles
BP-conjugated OPG Sox11-modified MSCs
Bone fracture SAA-loaded liposomes
l a n
o r p
e
r P
PDB
BP
Osteoclasts
SAON
Asp8-functionalized liposomes
Osteomyelitis
BP conjugated ciprofloxacin
Osteocytes and Decrease osteocytes apoptosis and increase osteoclatsogenesis osteoclasts and osteogenesis High turnover Improve the therapeutic index for osteomyelitis site
o J
ur
Reduce RANKL/OPG ratio
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(Zhao, et al., 2019) (He, et al., 2017) (Moreau, et al., 2011) (Pi, et al., 2015) (Doschak, et al., 2009)
(Xu, et al., 2015)
(Liu, et al., 2018) (Martini, et al., 2007) (Chen, et al., 2018) (Xie, et al., 2017)
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