Angiogenic factors in bone local environment

Cytokine & Growth Factor Reviews 24 (2013) 297–310

Contents lists available at SciVerse ScienceDirect

Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr

Survey

Angiogenic factors in bone local environment Shek Man Chim a, Jennifer Tickner a, Siu To Chow a, Vincent Kuek a, Baosheng Guo b, Ge Zhang b, Vicki Rosen c, Wendy Erber d, Jiake Xu a,* a

Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China c Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA d Translational Cancer Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia b

A R T I C L E I N F O

A B S T R A C T

Article history: Available online 20 April 2013

Angiogenesis plays an important role in physiological bone growth and remodeling, as well as in pathological bone disorders such as fracture repair, osteonecrosis, and tumor metastasis to bone. Vascularization is required for bone remodeling along the endosteal surface of trabecular bone or Haversian canals within the cortical bone, as well as the homeostasis of the cartilage-subchondral bone interface. Angiogenic factors, produced by cells from a basic multicellular unit (BMU) within the bone remodeling compartment (BRC) regulate local endothelial cells and pericytes. In this review, we discuss the expression and function of angiogenic factors produced by osteoclasts, osteoblasts and osteocytes in the BMU and in the cartilage-subchondral bone interface. These include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), BMP7, receptor activator of NF-kB ligand (RANKL) and epidermal growth factor (EGF)-like family members. In addition, the expression of EGFL2, EGFL3, EGFL5, EGFL6, EGFL7, EGFL8 and EGFL9 has been recently identified in the bone local environment, giving important clues to their possible roles in angiogenesis. Understanding the role of angiogenic factors in the bone microenvironment may help to develop novel therapeutic targets and diagnostic biomarkers for bone and joint diseases, such as osteoporosis, osteonecrosis, osteoarthritis, and delayed fracture healing. ß 2013 Elsevier Ltd. All rights reserved.

Keywords: Bone remodeling Angiogenesis EGF-like Bone remodeling compartment

Contents 1. 2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bone remodeling and angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . The bone remodeling compartment: a vascularized structure at the Angiogenic factors in bone remodeling compartment . . . . . . . . . . . . VEGF, bFGF and ET-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. RANKL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. 4.3. BMP7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EGF-like family members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

................ ................ site of remodeling. ................ ................ ................ ................ ................ ................ ................ ................

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

297 298 298 300 301 301 302 303 305 305 305

1. Introduction

* Corresponding author at: School of Pathology and Laboratory Medicine, 1st Floor, M Block, QEII Medical Centre, Nedlands, Australia. Tel.: +61 9346 2739; fax: +61 9346 2891. E-mail address: [email protected] (J. Xu). 1359-6101/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2013.03.008

Bone is a connective tissue that is characterized by a mixture of organic collagen and inorganic hydroxyapatite. It continuously undergoes remodeling to maintain skeletal size, shape and structural integrity. Angiogenesis plays a pivotal role during bone remodeling. Vasculature that supplies oxygen, nutrients, hormones, cytokines, as well as osteoblast and osteoclast precursor

298

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

cells, is important in bone remodeling. The bone remodeling compartment (BRC), an anatomical structure identified at the site of bone remodeling, is closely associated with blood vessels. The initiation of sprouting angiogenesis from existing bone vasculature toward the BRC and maintenance of newly formed vessels could be regulated by osteoclasts, osteoblasts, and osteocytes. Cumulative evidence shows that bone cells are capable of producing angiogenic factors, while the endothelium could contribute osteogenic factors, indicative of intercellular communication between bone cells and endothelial cells. In recent years, a role for EGF-like family members has been identified in bone biology, including factors such as EGF, heparin binding-EGF (HBEGF), transforming growth factor-alpha (TGFa), betacellulin (BTC), and EGF-like protein 6 (EGFL6). Interestingly, the EGF-like family also plays an important role in angiogenesis. This review aims to provide a summary focusing on the expression of angiogenic factors in the bone microenvironment, and the complex interrelationship between angiogenesis and osteogenesis. 2. Bone remodeling and angiogenesis Bone is a living tissue and, in order to maintain mechanical integrity, it is continuously undergoing remodeling [1]. Bone remodeling is accomplished by two important steps, bone resorption followed by new bone formation. Osteoclasts are the principal cells in bone resorption. Osteoclasts remove old and damaged bone by attachment to the bone surface and degradation of bone matrix. The resorption area is then filled with osteoblasts, which play an important role in bone mineralization and deposition of new bone matrix. The balancing act of osteoclasts and osteoblasts is essential in regulating the volume of bone resorption and deposition in order to maintain bone size and shape. Bone remodeling is tightly regulated by a multitude of local and systemic factors which control the cellular activities during the remodeling process [1–5]. An imbalance of osteoblastic bone formation and osteoclastic bone resorption will lead to various skeletal diseases. For example, increased osteoclastic bone resorption relative to bone formation would result in low bone mass and skeletal fragility, which is associated with bone lytic disorders such as osteoporosis and Paget’s disease. On the other hand, decreased osteoclastic bone resorption relative to bone formation is clinically associated with osteopetrosis [6,7]. The vasculature is important for skeletal development during the embryonic stage, postnatal growth and bone remodeling. Bone tissues are invaded by blood vessels which bring in precursors of osteoblasts and osteoclasts, nutrients, growth factors and differentiation factors [8,9]. During the embryonic stage, mesenchymal precartilage condensation occurs in the region of the embryonic limb bud where mesenchymal precursors differentiate into cartilage cells [10]. At this stage, immature blood vessels formed by endothelial cells invade the cartilage from the connective tissues surrounding the bone. This process is regulated by VEGF expression in chondrocytes undergoing differentiation [11,12]. In postnatal growth, the endothelial cells invade the cartilage at the growth plate region and form a vascular channel which provides access for the cells involved in bone formation [10]. The cartilage is gradually degraded by osteoclasts and replaced by osteoblasts, and subsequent ossification occurs. The vasculature also provides a scaffold for bone-forming cells and directs new bone formation [9,10,13,14]. Evidence has also been presented for a role for angiogenesis in the regulation of homeostasis of the cartilage-subchondral bone interface. Cartilage is avascular and resistant to vascular invasion, partly due to the expression of anti-angiogenic protease inhibitors [15], and high expression of chondromodulin-I (ChM-I) [16]. Vascular invasion can occur at the cartilage-subchondral bone

interface driven by increased expression of pro-angiogenic markers, and decreased expression of ChM-I [16,17]. Reduction in the expression levels of ChM-I from articular cartilage might cause the loss of resistance to vascularization, leading to blood vessel invasion into the cartilage. Abnormal angiogenesis that occurs at the cartilage-subchondral bone interface could potentially contribute to the progression of osteoarthritis. The cortical bone is associated with a network of capillaries, which is in continuity with periosteum and endosteum. Periosteum lines the outer surface of cortical bone and is covered by capillaries running in circular and longitudinal patterns along the bone. The endosteum is a highly vascular membrane lining the inner surface of cortical bone [18,19]. To link the vascular system between endosteum and periosteum a network of intracortical canals consisting of longitudinal Haversian canals and transversal Volkmann canals exists, which allows a continuous connection between periosteum and endosteum [20]. Collectively, as shown in Fig. 1, angiogenesis is an integral part of bone remodeling, taking place along the endosteal surface of trabecular bone, on the periosteal and endosteal surface and Haversian canals within the cortical bone, and at the cartilage-subchondral bone interface. Moreover, angiogenesis is important in fracture repair during hematoma formation, soft callus formation, hard callus formation and post-fracture bone remodeling [21]. It has been demonstrated that angiogenesis has an important role in bone formation during distraction osteogenesis and that it is under the regulation of angiogenic and osteogenic related genes such as VEGF, fibroblast growth factors (FGFs), and bone morphogenic proteins (BMPs). Conversely, inhibition of angiogenesis in distraction osteogenesis prevents normal osteogenesis during the healing processes and results in fibrous nonunion [22]. Recently, microvascular pericytes have been shown to have multilineage potential and to contribute to bone tissue formation [23,24]. Pericytes are relatively undifferentiated cells that wrap around the abluminal wall of blood vessels [25]. Pericytes have been shown to be capable of differentiating into osteoblasts, chondrocytes, adipocytes and fibroblasts [24,26,27]. It is well established that the platelet-derived growth factor (PDGF)-B/PDGFRb signaling pathway is critical in pericyte proliferation and recruitment [28]. PDGF-B is secreted by endothelial cells and regulates pericytes by a paracrine mechanism [28,29]. Moreover, a recent study suggested that EGF-like family member, HB-EGF regulates pericyte proliferation and recruitment along blood vessels [29]. Interestingly, PDGF-B and HB-EGF are also expressed by bone cells [30–32]. These findings indicate that bone cells could regulate pericytes in the bone local environment. The interaction between vasculature and bone remodeling at the cellular level is still unclear. Understanding the coupling process between bone endothelium and bone cells is vital for us to modulate bone homeostasis and develop novel targeted therapeutic approaches for bone diseases. Cumulative evidence demonstrates that numerous skeletal pathologies are strongly related to changes in vascularization; Paget’s disease of bone [2], osteopetrosis [33–35], osteoporosis [36,37], osteoarthritis [38], rickets [39,40], avascular necrosis [41– 43], inflammatory bone loss [44,45], multiple myeloma [46–48], and metastatic bone disease [49,50]. 3. The bone remodeling compartment: a vascularized structure at the site of remodeling Bone remodeling takes place in a specialized vascular structure called the BRC [51]. The BRC is a narrow sinus on the bone surface, which is formed between the bone marrow and the remodeling surface. When the bone remodeling process is initiated the lining cells of the endosteal membrane detach from the bone by disruption of the gap junctions to form the roof of the BRC

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

299

Fig. 1. Schematic diagram showing vascular supply in bone. Vascular supply is important for all regions of bone. Blood vessels invade into bone and provide nutrients and hormones required for development and remodeling at (A) trabecular bone within epiphysis, (B) cartilage-subchondral bone interface, (C) trabecular bone within diaphysis, and (D) cortical bone.

[5,52]. It is well accepted that capillaries are associated with the BRC. There are two hypothetical models of capillary orientation in the BRC. The association of capillaries with the BRC has been demonstrated using a 3D reconstructed model, suggesting that the communication between capillaries and BRC is through a contact point [53]. An alternative model has also been presented suggesting that capillaries might physically penetrate the canopy into the BRC [54,55]. It has been suggested that the association of blood vessels with the BRC via the canopy of cells is necessary to provide a vascular supply for the cells in the BRC and regulate the coupling between bone resorption and bone formation [56,57]. Importantly, pathological studies in multiple myeloma and Cushing’s syndrome demonstrated that the canopy of cells covering the BRC plays a critical role in bone remodeling [58,59]. A recent study suggested that coverage of BRC canopies is important during the whole remodeling process, including bone resorption by osteoclasts, recruitment and differentiation of osteoblasts, and bone formation by osteoblasts. Disruption of the coverage results in deficient bone restitution [58].

The BRCs most likely serve the following purposes: firstly, the BRC provides an anatomical structure that integrates with the microvasculature of bone and the process of bone remodeling. Cellular responses within the BRC are regulated by systemic hormones such as thyroid hormone, estrogen, vitamin D and parathyroid hormone (PTH), which are provided from the circulating blood supply. Moreover, osteoblast and osteoclast precursor cells within the blood supply have been shown to be recruited to the bone remodeling site [60,61]. Secondly, the BRC is an ideal compartment for the coupling between osteoblasts and osteoclasts. The membrane bound receptor activator of the NF-kB ligand (RANKL) expressed by osteoblasts is required for osteoclast differentiation and activation. Direct cell to cell interaction between osteoblast and osteoclast precursors is needed for osteoclast activation. The identification of lining cells in the canopy of the BRC, which exhibit an osteoblast phenotype and express RANKL, has shed light on this. These lining cells interact with osteoclast precursors which enter the BRC through the blood supply [3,5]. Thirdly, the BRC could be a structure to receive

300

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

Fig. 2. Schematic diagram showing hypothetical model of angiogenic processes regulated by osteocytes, osteoclasts and osteoblasts in BRC. Bone remodeling is initiated by stimuli such as microdamage. Damaged osteocytes produce angiogenic factors which lead angiogenic sprouting toward bone remodeling site. Osteoclast precursors are recruited into BRC and differentiated to mature osteoclast. Osteoclasts resorb bone, and also secrete angiogenic factors and release them from ECM. Osteoblast precursors are recruited into BRC. Osteoblasts synthesize osteoid to fill the space in BRC and also produce angiogenic factors during bone formation. Some osteoblasts differentiate into osteocytes and embedded in mineralized osteoid.

mechanosensory signals from the osteocyte network and trigger the remodeling events on the bone surface. The osteocyte plays a pivotal role in bone remodeling, they are the most numerous and longest-living cells in bone. Events of mechanical stress, such as microdamage to the bone could initiate bone remodeling events. The mechanical signal is transmitted to the lining cells through the gap junctions. The lining cells then release paracrine factors, such as insulin-like growth factor and prostaglandins, to stimulate the formation of osteoblasts from their precursor cells and the formation of new bone [5,62,63]. In addition, osteocyte apoptosis and microdamage in bone caused by skeletal loading or pathologic conditions could initiate bone remodeling [5,7]. Fourthly, the canopy serves to create a unique microenvironment that allows localization of signaling molecules to the site of bone remodeling. It has been postulated that the BRC serves to concentrate cytokines,

allowing them to reach critical mass by preventing them from dispersing within the marrow, and also protecting the cells within the BRC from high levels of activating cytokines in the marrow that could potentially cause unwanted effects [3]. It is understood that a directional sprouting of endothelial cells from existing vasculature toward the BRC is required in the initial step of bone remodeling, followed by formation of new blood vessels over BRC canopies. Here, we propose a hypothetical model of angiogenic processes regulated by osteoclasts, osteoblasts and osteocytes during bone remodeling (Fig. 2). 4. Angiogenic factors in bone remodeling compartment Locally produced angiogenic factors in the bone mircoenvironment are critical for bone remodeling. Osteoclasts, osteoblasts, and

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

osteocytes, three major cells in bone remodeling, could produce angiogenic factors which influence the directional angiogenesis and maintain the blood supply above BRC canopies during the entire remodeling cycle. Previous reviews identify a myriad of molecules produced by osteoblasts and osteoclasts that could regulate endothelial cell activities, including proliferation, migration, survival and angiogenesis [9]. Recently, osteocytes were found to play a pivotal role in the initiation of bone remodeling, via producing angiogenic factors, such as VEGF [64–66], RANKL [67,68] and BMP7 [69–71]. 4.1. VEGF, bFGF and ET-1 VEGF is a potent mitogen and angiogenic factor for endothelial cells and its role in the vascularization of bone tissues has been well characterized. VEGF interacts with two receptor tyrosine kinases, VEGFR-1 and VEGFR-2 to regulate endothelial cell activities [72–74]. VEGF is highly expressed in chondrocytes both in the lower hypertrophic and mineralized regions of the cartilage of developing embryonic bones. Angiogenesis in these areas is an important step toward ossification [11,75]. VEGF is also expressed during osteoblast differentiation, and its expression level is enhanced by stimulators of osteoblast differentiation such as IGF and Vitamin D3 [76,77]. The expression of VEGF receptors has been identified during primary osteoblast differentiation [78,79]. It has been demonstrated that VEGF acts as a potent chemoattractant for osteoblasts and osteoclasts [80,81]. Moreover, VEGF expression is upregulated during osteoclast differentiation through NF-kB induction of HIF-1a [82]. VEGF expression is also increased in direct response to hypoxia in osteoclasts, and hypoxia stimulates osteoclast formation [83]. In addition, osteoclasts express VEGF receptors and VEGF directly enhances osteoclastic bone resorption and osteoclast survival [40,84–87]. Interestingly, VEGF is also expressed in haematopoietic and endothelial cells regulated by TGFb1, a major cytokine released from the bone matrix during bone remodeling. This raises the possibility that TGFb1 released from osteoclasts could induce VEGF expression in cells within the BRC to help maintain the vascular supply [88,89]. Recent studies suggest that osteocytes are also a source of VEGF in the BRC. VEGF is released by MLO-Y4 osteocytes in response to mechanical loading by pulsatile fluid shear stress [65,66]. There is emerging evidence to demonstrate that microdamage to the bone could initiate osteocyte apoptosis and bone remodeling events [7,90,91]. In vitro studies have shown that VEGF expression significantly increased in osteocytes undergoing apoptosis induced by TNFa [64]. bFGF is a member of the FGF family which has pleiotropic effects on different cells and organ development in vitro and in vivo [92–95]. It is produced by various cells including fibroblasts, endothelial cells and osteoblasts [96–98]. bFGF is a potent mitogenic factor for several different cell types, including fibroblasts and endothelial cells. It induces angiogenesis through functioning as an autocrine and paracrine factor which stimulates endothelial cell proliferation, migration, and expression of proteases, growth factors and integrins involved in angiogenesis [99–102]. bFGF binds to its receptors FGFR-1, FGFR-2, FGFR-3 and FGFR-4 to activate signaling cascades that mediate endothelial cell activities [103–105]. Moreover, bFGF contributes significantly to bone development, remodeling, and repair [106–109]. bFGF is a strong stimulator of osteogenesis and adipogenesis and has been shown to have a strong stimulatory effect on bone formation in osteopenic ovariectomized rats [110]. In osteoblasts, bFGF was produced in response to prostaglandins and TGF-b [111–113]. bFGF also acts via autocrine and paracrine mechanisms to promote proliferation of osteoblast precursor cells and their differentiation into mature osteoblasts [114–116]. In osteoclasts, bFGF has been

301

shown to induce osteoclastogenesis by regulating the production of osteoclast differentiation factors such as RANKL and COX-2 [117–119]. It also regulates osteoclastic bone resorption through the activation of FGF receptor and ERK signaling pathways [120]. Using a chick embryo chorioallantoic membrane assay (CAM) implanted with a bone chip, it has been shown that bFGF promotes osteoclast recruitment, formation, differentiation, and resorption activity on bone at sites of stimulated angiogenesis [95]. During fracture repair, it has been demonstrated that mature osteoclasts produce heparanase. This functions to degrade heparin sulfate proteoglycans, a major component in ECM, and release heparin-binding growth factors including VEGF and bFGF, resulting in the promotion of angiogenesis, and regulation of osteoblast and osteoclast activity [95,121–123]. In addition, angiogenic factors such as VEGF, FGFs and their receptors are upregulated during distraction osteogenesis [22,124–126]. Conversely, inhibition of angiogenesis prevents fracture healing [22,127]. Rapamycin has anti-angiogenic activities and can cause delayed fracture healing via inhibiting neovascularization in the callus [128]. Moreover, shock waves have been shown to improve fracture healing and tendon repair by stimulating the production of VEGF in osteoblasts, which in turn induces angiogenesis [129]. In recent studies, endothelial cells have been shown to produce BMP-2 and BMP-4 when they are subjected to mechanical stimuli, VEGF, or hypoxic environments. BMPs potently stimulate osteoblast differentiation to promote fracture healing [9,130–132]. The intracellular Smad molecules in BMP signaling pathways can be regulated by protein degradation via ubiquitin-mediated proteasomal degradation [133]. We have recently identified casein kinase-2 interacting protein-1 (CKIP-1) as an auxiliary factor of ubiquitin ligase Smad ubiquitylation regulatory factor 1 (Smurf1) to ubiquitylate Smad1/ 5. As shown in Fig. 3, by interrupting the BMP signaling pathway, CKIP-1 not only down-regulates bone formation but also suppresses angiogenesis during bone fracture healing as evidenced by improved vascular structures found in CKIP-1 knockout mice (Dr. Zhang Ge, Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University). Endothelin-1 (ET-1) is expressed by endothelial cells and osteoblasts, and may play an important role in the regulation of angiogenesis and bone formation during bone remodeling [57,134–137]. There are two types of ET-1 receptors, ETA and ETB [138]. It has been suggested that ET-1 directly regulates angiogenesis by promoting endothelial cell migration, proliferation and differentiation, or indirectly by inducing VEGF production in endothelial cells [139–144]. ET-1 also regulates VEGF production in osteoblastic cells [145–147]. Interestingly, a study has revealed that the matrix mineralization in bone is disrupted in ET1 knockout mice [148]. It has been suggested that ET-1 stimulates both proliferation and differentiation of osteoblasts [149]. Taken together, these studies show that VEGF, bFGF and ET-1 regulate the communication between endothelial cells and bone cells via autocrine and paracrine mechanisms in the BRC. 4.2. RANKL The RANK/RANKL/osteoprotegerin (OPG) system has an essential role in bone biology, and has recently been identified as a regulator of vascular biology. RANKL binds as a homotrimer to its receptor (RANK) on osteoclast precursor cells and mature osteoclasts, and regulates multiple intracellular signaling pathways resulting in osteoclast differentiation and activation [150– 152]. The binding of RANKL to RANK on endothelial cells also plays an important role in maintaining endothelial cell survival through the PI3K/Akt signal transduction pathway [153]. RANKL also possesses angiogenic activity in vitro and in vivo. RANKL stimulates DNA synthesis, migration, and tube-like structure formation in

302

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

Fig. 3. Angiography of callus at 1 week and 2 weeks after fracture operation. The angiograph of callus from CKIP-1 knockout (KO) and wide-type (WT) mice was reconstructed by micro CT at 1 week and 2 weeks after fracture operation. Larger blood vessel volume was indicated in red color. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

endothelial cells in vitro. Using a Matrigel plug assay in mice, and a chick chorioallantoic membrane assay in vivo, RANKL has also been shown to potently induce angiogenesis. RANKL-induced angiogenic activity occurs through the activation of the mitogenactivated protein kinases ERK1/2 and focal adhesion kinase in a time- and dose-dependent manner [154]. RANKL actions are blocked by OPG, a soluble receptor expressed by a variety of cells including osteoblasts, stromal cells, and endothelial cells. OPG functions as a decoy receptor preventing RANKL/RANK interaction [45,155–158]. In addition, OPG and RANKL also affect endothelial cell survival and angiogenic activities. It was discovered that OPG mediates integrin-dependent survival of endothelial cells. The expression of OPG is induced by integrin avb3 binding to osteopontin [159]. OPG then directly binds and forms a complex with tumor necrosis factor-related apoptosis-inducing ligands (TRAIL) to prevent TRAIL interaction with apoptosis-inducing TRAIL receptors on endothelial cells [160]. OPG and RANKL expression in osteoblasts and bone marrow stromal cells is regulated by various stimuli such as PTH, Vitamin D3, prostaglandin E2, dexamethasone and IL-11. Interestingly, endothelial cells also produce both OPG and RANKL in response to stimuli, including

inflammatory cytokines TNF-a and IL-1a, but not PTH and Vitamin D3 [45,161–163]. It has also been suggested that the RANKL/RANK/ OPG system mediates the process of vascular calcification [157]. Osteocytes are also a major source of RANKL. RANKL is secreted by damaged MLO-Y4 osteocytes after mechanical scratching [164]. Conditional knockout models have recently identified osteocytes as the major producer of RANKL controlling postnatal bone remodeling [68]. 4.3. BMP7 BMPs belong to the TGFb superfamily. The binding of BMPs to BMP type I and type II receptors regulates downstream signaling molecules, such as Smad and MAPK [165,166]. BMPs play essential roles in skeletal embryogenesis, cartilage development and bone formation [132,167]. Moreover, BMPs regulate proliferation and migration of endothelial cells, and are important in angiogenesis [165,166]. A recent study in a zebra fish model suggested that BMPs play a distinct role in angiogenic sprouting of venous endothelial cells. In this study, it was demonstrated that sprouting angiogenesis in the dorsal aorta is driven by VEGF signaling, but

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

not BMP signaling, whereas sprouting angiogenesis in the axial vein is regulated by BMPs through the activation of Smad and Erk1/ 2 [166]. BMP7 binds to BMP type II receptors, A (BMPRII ctRIIA, ActRIIB), and Type I receptors (ALK2/3/6) [165]. It has been suggested that BMP7 promotes endothelial cell survival [71] and induces angiogenesis [168] indirectly by increasing VEGF expression [169]. Interestingly, BMP7 expression has been detected in osteocytes [69,70], osteoclasts [170,171] and osteoblasts [69,172]. Immunohistochemical staining revealed that osteoblasts and osteocytes expressed BMP7 at the endosteal surface of cortical bone [69,70]. Like VEGF, BMP7 gene and protein expression is upregulated in osteocytes in response to mechanical loading by pulsatile fluid shear stress [69]. 4.4. EGF-like family members EGF has been shown to directly stimulate epidermal growth and keratinization [173,174], and play an important role in angiogenesis [175]. EGF is a single polypeptide chain consisting of 53 amino acid residues. It is characterized by three intramolecular disulfide bonds formed by interactions between spatially cysteine residues. These disulfide bonds are important for the biological activity of EGF, and a disruption to these disulfide bonds could result in inactivation of EGF [176,177]. EGF-like proteins, which contain single or multiple EGF-like repeats have been identified as

303

membrane-bound proteins or secreted proteins. The EGF-like domains contain 30–40 amino acid residues that have significant homology to EGF. The EGF-like domains are characterized by a consensus sequence consisting of six spatially conserved cysteine residues forming three disulfide bonds [178–181]. The spatially conserved disulphide bridges of the EGF-like proteins result in a similar secondary structure to EGF. It has been suggested that these highly homologous domains share some common functional features [178,180,182,183]. EGF-like factors mediate their biological effects through binding to a group of four transmembrane tyrosine kinase receptors, including EGFR, ErbB2, ErbB3 and ErbB4. The activation of EGF receptors triggers numerous intracellular signaling cascades, including PI3 kinase, MAP kinase and STAT pathways [183–187]. The EGF ligand family comprises typical members; including EGF, HB-EGF, BTC, TGFa, Epigen (EPGN), amphiregulin (AREG), epiregulin (EREG) and neuregulins (NRG1-4) [183]. Interestingly, NRGs also belong to a complex growth factor family which encodes NRG1-4, which all contain an EGF-like domain. NRGs have been reported to produce many isoforms by alternative splicing [188,189]. EGF-like factors usually require proteolytic cleavage to release mature soluble EGF-like domains which bind and activate EGF receptors [183,186]. However, membrane associated EGF family members such as EGF, HB-EGF, and TGFa can act as juxtacrine factors to regulate cellular activities [190–193]. It has

Fig. 4. Schematic representations of domain structures of EGF-like family members. EGF-like family members contain differing number of EGF domains and vary in amino acid length.

304

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

become clear that EGF-like family members play an important role in bone biology [194,195]. EGF receptors are expressed in a number of cell types, including osteoblasts, osteoclasts, and endothelial cells [196–199]. Interestingly, there is accumulating evidence demonstrating that EGF-like family members might facilitate the communication between osteoclasts, osteoblasts and endothelial cells that is essential for the bone remodeling process. The expression of EGF-like family members has been detected in osteoblasts, osteoclasts and endothelial cells. To date, it has been demonstrated that EGF, HB-EGF, AREG, EREG, and NRG are expressed during osteoclast differentiation [31]. Osteoblasts express EGF, HB-EGF, AREG, BTC, EREG and TGFa [32,200]. Recently, EGF-like genes such as EGFL2, EGFL3, EGFL5, EGFL6, EGFL7, EGFL8 and EGFL9 were found differentially expressed in the BMU [201]. EGFL3, EGFL5, EGFL6 and EGFL9 were preferentially expressed in osteoblasts, whereas EGFL2, EGFL7 and EGFL8 were expressed abundantly in both osteoclasts and osteoblasts. EGF-like family members are predicted as membrane-bound or secreted proteins. EGFL2, EGFL5 and EGFL9 contain transmembrane domains, whereas EGFL3, EGFL6, EGFL7 and EGFL8 lack transmembrane domains [201]. Schematic representations of EGF-like family members are shown in Fig. 4. EGF-like family members vary in amino acid length and contain differing number of EGF domains. Among all EGFL members, EGF, HB-EGF, TGFa, BTC and EGFL7 are also expressed in endothelial cells, indicative of both an autocrine and paracrine regulation [198,202–208]. EGF and some of the EGF-like members are angiogenic factors. It was demonstrated that EGF had angiogenic activity in vivo using a rabbit cornea model [175]. EGF significantly promotes human umbilical vein endothelial cell and tumor endothelial cell proliferation [209,210]. It has also been demonstrated that EGF can induce endothelial cell migration and tube formation in vitro via the activation of PI3K and MAPK signaling pathways [198,211]. Similarly, HB-EGF also induces angiogenesis through the activation of PI3K and MAPK signaling pathways [198]. Moreover, HB-EGF induces endothelial cell migration by stimulating endothelial nitric oxide synthase and nitric oxide production [212]. BTC plays an important role in hair follicle development and hair cycle

induction. In a wound healing experiment, it has been demonstrated that the area covered by blood vessels was significantly increased in transgenic mice overexpressing BTC. The blood vessel size and density in BTC transgenic mice were also increased [213]. Moreover, it was shown that BTC induces endothelial cell migration and tube formation through the activation of ERK1/2 and AKT signaling pathways [184]. TGFa has been demonstrated as a potent chemoattractant for endothelial cells [214]. It stimulated extensive formation of new capillaries in a hamster cheek pouch assay in vivo [215]. Subsequently, a study has found that treatment with TGFa significantly increases blood vessel area surrounding infarct site in a brain injury model [216]. AREG has been implicated in tumor angiogenesis. It has been demonstrated that inhibition of AREG significantly reduced vascular density and size of tumors [217–221]. NRG1 is the most well studied member of NRG family that shares the common EGF-like domain that is critical for its function. NRG1 plays a important role in cardiovascular biology by regulating blood pressure and angiogenesis [222]. Recently, it has been reported that EGFL6 induces angiogenesis by a paracrine mechanism in which EGFL6 is expressed in osteoblastic like cells but promotes migration and angiogenesis of endothelial cells. It has been demonstrated that EGFL6 gene and protein expression is upregulated during osteoblast differentiation. In addition, EGFL6 proteins were expressed during bone development. Interestingly, EGFL6 induces endothelial cell migration and tube-like structure formation via the activation of ERK1/2. EGFL6 might interact with integrins to regulate endothelial cell activities [201]. EGFL2, EGFL3, EGFL5, EGFL6, EGFL8 and EGFL9 are relatively newly identified EGF-like family members, and their cellular functions are still not fully understood. However, they contain EGF domains which could potentially regulate endothelial cell activities through EGF receptors. Notably, they are abundantly expressed in osteoblastic like cells, raising the possibility that these EGF-like family proteins might play an important role in angiogenesis and bone biology. EGFL7 has been recently identified in osteoclasts and osteoblasts [201]. It has been demonstrated that EGFL7 induces endothelial cell migration and plays an important role in

Fig. 5. Angiogenic factors produced in BRC. BRC is closely associated with blood vessels, which provide essential nutrients, and recruiting osteoclast and osteoblast precursor cells to bone remodeling site. Angiogenic factors such as VEGF, bFGF, ET-1, RANKL, BMP7 and EGF-like family members are produced by osteoclasts and osteoblasts, and regulate endothelial cell activities above the BRC canopies.

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

305

Table 1 Expression of angiogenic factors in BRC and their roles in angiogenic activities. Angiogenic factors

Receptors

Angiogenic activities

Expression in osteoblasts

Expression in osteocytes

Expression in osteoclasts

VEGF

VEGFR1, VEGFR2

H [76,77]

H [64–66]

H [82]

bFGF ET-1 RANKL BMP7 EGF HB-EGF TGFa EGFL6 EGFL7 AREG BTC

FGFR1, FGFR2, FGFR3, FGFR4 ETA, ETB RANK BMPRII, ActRIIA, ActRIIB, ALK2/3/6 EGFR EGFR, ErbB4 EGFR EGFRs (potential), Integrins EGFR, Notch EGFR EGFR, ErbB4

Proliferation, migration, survival, angiogenesis [73]. Induction of MMPs [74] Proliferation, migration, survival, angiogenesis [99,100] Proliferation, migration, angiogenesis [139–144] Migration, survival, angiogenesis [153,154] Proliferation, survival, angiogenesis[71,168] Proliferation, migration, angiogenesis [198,209,210] Migration, angiogenesis [198,212] Proliferation, migration, angiogenesis [208,214,215] Migration, angiogenesis [201] Migration, angiogenesis [203,223–225] Angiogenesis [217–221] Migration, angiogenesis[184,213]

? ? H [67,68] H [69,70] ? ? ? ? ? ? ?

? ?  [150–152] H [170] H [31] H [31] ?  [201] H [201] H [31] ?

H H H H H H H H H H H

[97,98] [137] [150–152] [69,172] [199,200] [32,200] [200] [201] [201] [200] [200]

H, Expression was detected; , no expression was detected; and ?, expression was not reported.

tubulogenesis, the process by which blood vessels form during embryogenesis [203,223,224]. EGFL7-knockout mice were characterized by a severe delay in the development of the vasculature, and 50% of knockout embryos die in utero. EGFL7 regulates migration of endothelial cells and spatial organization in angiogenic sprouts [225]. EGFL7 has been shown to function through EGFR. Inhibition of EGFR significantly impaired EGFL7induced cell motility [226]. Moreover, EGFL7 also acts as an antagonist to Notch and regulates ligand-mediated receptor signaling [227]. The expression of angiogenic factors in the BRC and their roles in endothelial cell activities are summarized in Fig. 5 and Table 1. There are many other angiogenic factors which might play distinct roles in the BRC, such as interleukins and TGFb. The discovery of angiogenic factors in the BRC expands the knowledge of bone vascular biology, and may facilitate the development of therapeutic strategies for the treatment of skeletal disease associated with pathological angiogenesis. 5. Conclusion Vasculature of bone is important for skeletal development during the embryonic stage, postnatal growth, and bone remodeling. However, the role of angiogenesis and local angiogenic factors produced in the BRC remain to be fully elucidated. Formation of blood vessels near the BRC canopy is necessary for the bone remodeling process. The directional sprouting of endothelial cells toward the BRC could be driven by angiogenic factors expressed within the BRC. Interestingly, evidence shows that EGF-like family members could play an important role in angiogenesis. It is possible that EGF family members might fulfill a vital role in the cross-talk between bone cells and endothelial cells during bone remodeling. Moreover, aberrant angiogenesis is closely associated with many bone pathologies, including delayed bone fracture repair, osteoarthritis and osteonecrosis. Thus, understanding of the intercellular communication between bone endothelium and bone cells is vital for us to modulate bone homeostasis and develop novel targeted therapeutic approaches for bone diseases, such as osteoporosis, osteonecrosis, osteoarthritis, and delayed fracture healing. Disclosure All authors state that they have no conflicts of interest. Acknowledgments This work was funded in part by National Health and Medical Research Council of Australia, Western Australia Medical & Health Research Infrastructure Fund, and a grant from the National

Natural Science Foundation of China (NSFC, no. 81228013). Professor Vicki Rosen was an Australia-Harvard Fellow to the School of Pathology and Laboratory Medicine, the University of Western Australia in 2012. References [1] Gonzalez EA. The role of cytokines in skeletal remodelling: possible consequences for renal osteodystrophy. Nephrology Dialysis Transplantation 2000;15:945–50. [2] Mundy GR. Cellular and molecular regulation of bone turnover. Bone 1999;24:8S–35S. [3] Eriksen EF, Eghbali-Fatourechi GZ, Khosla S. Remodeling and vascular spaces in bone. Journal of Bone and Mineral Research 2007;22:1–6. [4] Hadjidakis DJ, Androulakis II. Bone remodeling. Annals of the New York Academy of Sciences 2006;1092:385–96. [5] Martin TJ, Seeman E. Bone remodelling: its local regulation and the emergence of bone fragility. Best Practice and Research Clinical Endocrinology and Metabolism 2008;22:701–22. [6] Iacovino JR. Mortality outcomes after osteoporotic fractures in men and women. Journal of Insurance Medicine 2001;33:316–20. [7] Kular J, Tickner J, Chim SM, Xu J. An overview of the regulation of bone remodelling at the cellular level. Clinical Biochemistry 2012;45:863–73. [8] Trueta J, Buhr AJ. The vascular contribution to osteogenesis. V. The vasculature supplying the epiphysial cartilage in rachitic rats. Journal of Bone and Joint Surgery British Volume 1963;45:572–81. [9] Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. Journal of Bone and Mineral Research 2006;21:183–92. [10] Gerber HP, Ferrara N. Angiogenesis and bone growth. Trends in Cardiovascular Medicine 2000;10:223–8. [11] Carlevaro MF, Cermelli S, Cancedda R, Descalzi Cancedda F. Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. Journal of Cell Science 2000;113(Pt 1):59–69. [12] Burkus JK, Ganey TM, Ogden JA. Development of the cartilage canals and the secondary center of ossification in the distal chondroepiphysis of the prenatal human femur. Yale Journal of Biology and Medicine 1993;66:193–202. [13] Collin-Osdoby P. Role of vascular endothelial cells in bone biology. Journal of Cellular Biochemistry 1994;55:304–9. [14] Streeten EA, Brandi ML. Biology of bone endothelial cells. Bone and Mineral 1990;10:85–94. [15] Franses RE, McWilliams DF, Mapp PI, Walsh DA. Osteochondral angiogenesis and increased protease inhibitor expression in OA. Osteoarthritis and Cartilage 2010;18:563–71. [16] Hayami T, Funaki H, Yaoeda K, Mitui K, Yamagiwa H, Tokunaga K, et al. Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis. Journal of Rheumatology 2003;30:2207–17. [17] Wang QY, Dai J, Kuang B, Zhang J, Yu SB, Duan YZ, et al. Osteochondral angiogenesis in rat mandibular condyles with osteoarthritis-like changes. Archives of Oral Biology 2012;57:620–9. [18] Trias A, Fery A. Cortical circulation of long bones. Journal of Bone and Joint Surgery 1979;61:1052–9. [19] Simpson AH. The blood supply of the periosteum. Journal of Anatomy 1985;140(Pt 4):697–704. [20] Pazzaglia UE, Zarattini G, Giacomini D, Rodella L, Menti AM, Feltrin G. Morphometric analysis of the canal system of cortical bone: an experimental study in the rabbit femur carried out with standard histology and micro-CT. Anatomia Histologia Embryologia 2010;39:17–26. [21] Carano RA, Filvaroff EH. Angiogenesis and bone repair. Drug Discovery Today 2003;8:980–9.

306

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310

[22] Fang TD, Salim A, Xia W, Nacamuli RP, Guccione S, Song HM, et al. Angiogenesis is required for successful bone induction during distraction osteogenesis. Journal of Bone and Mineral Research 2005;20:1114–24. [23] Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, et al. Multilineage potential of cells from the artery wall. Circulation 2003;108:2505–10. [24] Gerhardt H, Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell and Tissue Research 2003;314:15–23. [25] Dore-Duffy P. Pericytes: pluripotent cells of the blood brain barrier. Current Pharmaceutical Design 2008;14:1581–93. [26] Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE. Vascular pericytes express osteogenic potential in vitro and in vivo. Journal of Bone and Mineral Research 1998;13:828–38. [27] Diaz-Flores L, Gutierrez R, Lopez-Alonso A, Gonzalez R, Varela H. Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clinical Orthopaedics and Related Research 1992;280–6. [28] Bergers G, Song S. The role of pericytes in blood–vessel formation and maintenance. Neuro-Oncology 2005;7:452–64. [29] Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGFBB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 2010;116:4720–30. [30] Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B. Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. PLoS ONE 2008;3:e3537. [31] Yi T, Lee HL, Cha JH, Ko SI, Kim HJ, Shin HI, et al. Epidermal growth factor receptor regulates osteoclast differentiation and survival through cross-talking with RANK signaling. Journal of Cellular Physiology 2008;217: 409–22. [32] Nakamura T, Toita H, Yoshimoto A, Nishimura D, Takagi T, Ogawa T, et al. Potential involvement of Twist2 and Erk in the regulation of osteoblastogenesis by HB-EGF-EGFR signaling. Cell Structure and Function 2010;35:53–61. [33] Marks Jr SC. Osteopetrosis in the toothless (t1) rat: presence of osteoclasts but failure to respond to parathyroid extract or to be cured by infusion of spleen or bone marrow cells from normal littermates. American Journal of Anatomy 1977;149:289–97. [34] Wisner-Lynch LA, Shalhoub V, Marks Jr SC. Administration of colony stimulating factor-1 to toothless osteopetrotic rats normalizes osteoblast, but not osteoclast, gene expression. Bone 1995;16:611–8. [35] Aharinejad S, Grossschmidt K, Franz P, Streicher J, Nourani F, MacKay CA, et al. Auditory ossicle abnormalities and hearing loss in the toothless (osteopetrotic) mutation in the rat and their improvement after treatment with colony-stimulating factor-1. Journal of Bone and Mineral Research 1999;14:415–23. [36] Alagiakrishnan K, Juby A, Hanley D, Tymchak W, Sclater A. Role of vascular factors in osteoporosis. Journals of Gerontology Series A Biological Sciences and Medical Sciences 2003;58:362–6. [37] Reeve J, Arlot M, Wootton R, Edouard C, Tellez M, Hesp R, et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. Journal of Clinical Endocrinology and Metabolism 1988;66:1124–31. [38] Ashraf S, Walsh DA. Angiogenesis in osteoarthritis. Current Opinion in Rheumatology 2008;20:573–80. [39] Tong A, Reich A, Genin O, Pines M, Monsonego-Ornan E. Expression of chicken 75-kDa gelatinase B-like enzyme in perivascular chondrocytes suggests its role in vascularization of the growth plate. Journal of Bone and Mineral Research 2003;18:1443–52. [40] Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, et al. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. Journal of Cell Biology 2000;151:879–89. [41] Smith DW. Is avascular necrosis of the femoral head the result of inhibition of angiogenesis? Medical Hypotheses 1997;49:497–500. [42] Thiele J, Rompcik V, Wagner S, Fischer R. Vascular architecture and collagen type IV in primary myelofibrosis and polycythaemia vera: an immunomorphometric study on trephine biopsies of the bone marrow. British Journal of Haematology 1992;80:227–34. [43] Thornton MJ, O’Sullivan G, Williams MP, Hughes PM. Avascular necrosis of bone following an intensified chemotherapy regimen including high dose steroids. Clinical Radiology 1997;52:607–12. [44] Collin-Osdoby P, Rothe L, Bekker S, Anderson F, Huang Y, Osdoby P. Development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro. Journal of Bone and Mineral Research 2002;17:1859–71. [45] Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P. Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. Journal of Biological Chemistry 2001;276: 20659–72. [46] Kumar S, Witzig TE, Greipp PR, Rajkumar SV. Bone marrow angiogenesis and circulating plasma cells in multiple myeloma. British Journal of Haematology 2003;122:272–4. [47] Asosingh K, De Raeve H, Menu E, Van Riet I, Van Marck E, Van Camp B, et al. Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity. Blood 2004;103:3131–7. [48] Vacca A, Ribatti D, Roccaro AM, Frigeri A, Dammacco F. Bone marrow angiogenesis in patients with active multiple myeloma. Seminars in Oncology 2001;28:543–50.

[49] Peyruchaud O, Serre CM, NicAmhlaoibh R, Fournier P, Clezardin P. Angiostatin inhibits bone metastasis formation in nude mice through a direct anti-osteoclastic activity. Journal of Biological Chemistry 2003;278:45826–32. [50] Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Research 2002;62:1832–7. [51] Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. Journal of Bone and Mineral Research 2001;16:1575–82. [52] Parfitt AM. The bone remodeling compartment: a circulatory function for bone lining cells. Journal of Bone and Mineral Research 2001;16:1583–5. [53] Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge EM, et al. A physical mechanism for coupling bone resorption and formation in adult human bone. American Journal of Pathology 2009;174: 239–47. [54] McGee-Lawrence ME, Westendorf JJ. Histone deacetylases in skeletal development and bone mass maintenance. Gene 2011;474:1–11. [55] Feng X, McDonald JM. Disorders of bone remodeling. Annual Review of Pathology 2011;6:121–45. [56] Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. Journal of Cellular Biochemistry 1994;55:273–86. [57] Parfitt AM. The mechanism of coupling: a role for the vasculature. Bone 2000;26:319–23. [58] Jensen PR, Andersen TL, Soe K, Hauge EM, Bollerslev J, Amling M, et al. Premature loss of bone remodeling compartment canopies is associated with deficient bone formation: a study of healthy individuals and patients with Cushing’s syndrome. Journal of Bone and Mineral Research 2012;27:770–80. [59] Andersen TL, Soe K, Sondergaard TE, Plesner T, Delaisse JM. Myeloma cellinduced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast–myeloma hybrid cells. British Journal of Haematology 2010;148:551–61. [60] Kindle L, Rothe L, Kriss M, Osdoby P, Collin-Osdoby P. Human microvascular endothelial cell activation by IL-1 and TNF-alpha stimulates the adhesion and transendothelial migration of circulating human CD14+ monocytes that develop with RANKL into functional osteoclasts. Journal of Bone and Mineral Research 2006;21:193–206. [61] De Becker A, Van Hummelen P, Bakkus M, Vande Broek I, De Wever J, De Waele M, et al. Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica 2007;92:440–9. [62] Marotti G, Ferretti M, Muglia MA, Palumbo C, Palazzini S. A quantitative evaluation of osteoblast–osteocyte relationships on growing endosteal surface of rabbit tibiae. Bone 1992;13:363–8. [63] Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcified Tissue International 1995;57:344–58. [64] Cheung WY, Liu C, Tonelli-Zasarsky RM, Simmons CA, You L. Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. Journal of Orthopaedic Research 2011;29:523–30. [65] Thi MM, Suadicani SO, Spray DC. Fluid flow-induced soluble vascular endothelial growth factor isoforms regulate actin adaptation in osteoblasts. Journal of Biological Chemistry 2010;285:30931–41. [66] Juffer P, Jaspers RT, Lips P, Bakker AD, Klein-Nulend J. Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes. American Journal of Physiology Endocrinology and Metabolism 2012;302: E389–95. [67] Zhao S, Zhang YK, Harris S, Ahuja SS, Bonewald LF. MLO-Y4 osteocyte-like cells support osteoclast formation and activation. Journal of Bone and Mineral Research 2002;17:2068–79. [68] Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature Medicine 2011;17:1231–4. [69] Santos A, Bakker AD, Willems HM, Bravenboer N, Bronckers AL, Klein-Nulend J. Mechanical loading stimulates BMP7, but not BMP2, production by osteocytes. Calcified Tissue International 2011;89:318–26. [70] Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, et al. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. Journal of Biological Chemistry 2010;285:41614–26. [71] Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, Karoubi G, Courtman DW, Zucco L, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circulation Research 2006;98:209–17. [72] Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling – in control of vascular function. Nature Reviews Molecular Cell Biology 2006;7:359–71. [73] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature Medicine 2003;9:669–76. [74] Heo SH, Choi YJ, Ryoo HM, Cho JY. Expression profiling of ETS and MMP factors in VEGF-activated endothelial cells: role of MMP-10 in VEGF-induced angiogenesis. Journal of Cellular Physiology 2010;224:734–42. [75] Horner A, Bishop NJ, Bord S, Beeton C, Kelsall AW, Coleman N, et al. Immunolocalisation of vascular endothelial growth factor (VEGF) in human neonatal growth plate cartilage. Journal of Anatomy 1999;194(Pt 4):519–24.

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310 [76] Schlaeppi JM, Gutzwiller S, Finkenzeller G, Fournier B. 1,25-Dihydroxyvitamin D3 induces the expression of vascular endothelial growth factor in osteoblastic cells. Endocrine Research 1997;23:213–29. [77] Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL. Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2alpha. Endocrinology 2002;143:420–5. [78] Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochemical and Biophysical Research Communications 1994;199:380–6. [79] Deckers MM, Karperien M, van der Bent C, Yamashita T, Papapoulos SE, Lowik CW. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 2000;141:1667–74. [80] Mayr-Wohlfart U, Waltenberger J, Hausser H, Kessler S, Gunther KP, Dehio C, et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone 2002;30:472–7. [81] Henriksen K, Karsdal M, Delaisse JM, Engsig MT. RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism. Journal of Biological Chemistry 2003;278: 48745–53. [82] Trebec-Reynolds DP, Voronov I, Heersche JN, Manolson MF. VEGF-A expression in osteoclasts is regulated by NF-kappaB induction of HIF-1alpha. Journal of Cellular Biochemistry 2010;110:343–51. [83] Utting JC, Flanagan AM, Brandao-Burch A, Orriss IR, Arnett TR. Hypoxia stimulates osteoclast formation from human peripheral blood. Cell Biochemistry and Function 2010;28:374–80. [84] Zelzer E, McLean W, Ng YS, Fukai N, Reginato AM, Lovejoy S, et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 2002;129:1893–904. [85] Nakagawa M, Kaneda T, Arakawa T, Morita S, Sato T, Yomada T, et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Letters 2000;473:161–4. [86] Niida S, Kaku M, Amano H, Yoshida H, Kataoka H, Nishikawa S, et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. Journal of Experimental Medicine 1999;190:293–8. [87] Harper J, Gerstenfeld LC, Klagsbrun M. Neuropilin-1 expression in osteogenic cells: down-regulation during differentiation of osteoblasts into osteocytes. Journal of Cellular Biochemistry 2001;81:82–92. [88] Shao ES, Lin L, Yao YC, Bostrom KI. Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood 2009;114:2197–206. [89] He C, Chen X. Transcription regulation of the vegf gene by the BMP/Smad pathway in the angioblast of zebrafish embryos. Biochemical and Biophysical Research Communications 2005;329:324–30. [90] Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. Journal of Bone and Mineral Research 2000;15:60–7. [91] Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metabolism 2007;5:464–75. [92] Klagsbrun M. The fibroblast growth factor family: structural and biological properties. Progress in Growth Factor Research 1989;1:207–35. [93] Mason IJ. The ins and outs of fibroblast growth factors. Cell 1994;78:547–52. [94] Bikfalvi A, Klein S, Pintucci G, Rifkin DB. Biological roles of fibroblast growth factor-2. Endocrine Reviews 1997;18:26–45. [95] Collin-Osdoby P, Rothe L, Bekker S, Anderson F, Huang Y, Osdoby P. Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro. Journal of Bone and Mineral Research 2002;17:1859–71. [96] Sato Y, Shimada T, Takaki R. Autocrinological role of basic fibroblast growth factor on tube formation of vascular endothelial cells in vitro. Biochemical and Biophysical Research Communications 1991;180:1098–102. [97] Globus RK, Plouet J, Gospodarowicz D. Cultured bovine bone cells synthesize basic fibroblast growth factor and store it in their extracellular matrix. Endocrinology 1989;124:1539–47. [98] Montero A, Okada Y, Tomita M, Ito M, Tsurukami H, Nakamura T, et al. Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. Journal of Clinical Investigation 2000;105:1085–93. [99] Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. Journal of Cell Biology 1998;141:1659–73. [100] Beck Jr L, D’Amore PA. Vascular development: cellular and molecular regulation. FASEB Journal 1997;11:365–73. [101] Klein S, Giancotti FG, Presta M, Albelda SM, Buck CA, Rifkin DB. Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. Molecular Biology of the Cell 1993;4:973–82. [102] Klein S, Bikfalvi A, Birkenmeier TM, Giancotti FG, Rifkin DB. Integrin regulation by endogenous expression of 18-kDa fibroblast growth factor-2. Journal of Biological Chemistry 1996;271:22583–90. [103] Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. Receptor specificity of the fibroblast growth factor family. Journal of Biological Chemistry 1996;271:15292–97.

307

[104] Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nature Reviews Cancer 2010;10:116–29. [105] Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine and Growth Factor Reviews 2005;16:159–78. [106] Boyce BF, Hughes DE, Wright KR, Xing L, Dai A. Recent advances in bone biology provide insight into the pathogenesis of bone diseases. Laboratory Investigation 1999;79:83–94. [107] Goldfarb M. Functions of fibroblast growth factors in vertebrate development. Cytokine and Growth Factor Reviews 1996;7:311–25. [108] Marie P, Debiais F, Cohen-Solal M, de Vernejoul MC. New factors controlling bone remodeling. Joint Bone Spine 2000;67:150–6. [109] Arman E, Haffner-Krausz R, Gorivodsky M, Lonai P. Fgfr2 is required for limb outgrowth and lung-branching morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 1999;96: 11895–99. [110] Aguirre JI, Leal ME, Rivera MF, Vanegas SM, Jorgensen M, Wronski TJ. Effects of basic fibroblast growth factor and a prostaglandin E2 receptor subtype 4 agonist on osteoblastogenesis and adipogenesis in aged ovariectomized rats. Journal of Bone and Mineral Research 2007;22:877–88. [111] Sabbieti MG, Marchetti L, Gabrielli MG, Menghi M, Materazzi S, Menghi G, et al. Prostaglandins differently regulate FGF-2 and FGF receptor expression and induce nuclear translocation in osteoblasts via MAPK kinase. Cell and Tissue Research 2005;319:267–78. [112] Sobue T, Gravely T, Hand A, Min YK, Pilbeam C, Raisz LG, et al. Regulation of fibroblast growth factor 2 and fibroblast growth factor receptors by transforming growth factor beta in human osteoblastic MG-63 cells. Journal of Bone and Mineral Research 2002;17:502–12. [113] Sabbieti MG, Marchetti L, Abreu C, Montero A, Hand AR, Raisz LG, et al. Prostaglandins regulate the expression of fibroblast growth factor-2 in bone. Endocrinology 1999;140:434–44. [114] Hanada K, Dennis JE, Caplan AI. Stimulatory effects of basic fibroblast growth factor and bone morphogenetic protein-2 on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Journal of Bone and Mineral Research 1997;12:1606–14. [115] Pitaru S, Kotev-Emeth S, Noff D, Kaffuler S, Savion N. Effect of basic fibroblast growth factor on the growth and differentiation of adult stromal bone marrow cells: enhanced development of mineralized bone-like tissue in culture. Journal of Bone and Mineral Research 1993;8:919–29. [116] Debiais F, Hott M, Graulet AM, Marie PJ. The effects of fibroblast growth factor-2 on human neonatal calvaria osteoblastic cells are differentiation stage specific. Journal of Bone and Mineral Research 1998;13:645–54. [117] Nakagawa N, Yasuda H, Yano K, Mochizuki S, Kobayashi N, Fujimoto H, et al. Basic fibroblast growth factor induces osteoclast formation by reciprocally regulating the production of osteoclast differentiation factor and osteoclastogenesis inhibitory factor in mouse osteoblastic cells. Biochemical and Biophysical Research Communications 1999;265:158–63. [118] Kawaguchi H, Chikazu D, Nakamura K, Kumegawa M, Hakeda Y. Direct and indirect actions of fibroblast growth factor 2 on osteoclastic bone resorption in cultures. Journal of Bone and Mineral Research 2000;15:466–73. [119] Hurley MM, Lee SK, Raisz LG, Bernecker P, Lorenzo J. Basic fibroblast growth factor induces osteoclast formation in murine bone marrow cultures. Bone 1998;22:309–16. [120] Chikazu D, Hakeda Y, Ogata N, Nemoto K, Itabashi A, Takato T, et al. Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase. Journal of Biological Chemistry 2000;275:31444–50. [121] Sato Y, Rifkin DB. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. Journal of Cell Biology 1988;107:1199–205. [122] Padera R, Venkataraman G, Berry D, Godavarti R, Sasisekharan R. FGF-2/ fibroblast growth factor receptor/heparin-like glycosaminoglycan interactions: a compensation model for FGF-2 signaling. FASEB Journal 1999;13:1677–87. [123] Saijo M, Kitazawa R, Nakajima M, Kurosaka M, Maeda S, Kitazawa S. Heparanase mRNA expression during fracture repair in mice. Histochemistry and Cell Biology 2003;120:493–503. [124] Pacicca DM, Patel N, Lee C, Salisbury K, Lehmann W, Carvalho R, et al. Expression of angiogenic factors during distraction osteogenesis. Bone 2003;33:889–98. [125] Miyanishi K, Trindade MC, Ma T, Goodman SB, Schurman DJ, Smith RL. Periprosthetic osteolysis: induction of vascular endothelial growth factor from human monocyte/macrophages by orthopaedic biomaterial particles. Journal of Bone and Mineral Research 2003;18:1573–83. [126] Hu J, Zou S, Li J, Chen Y, Wang D, Gao Z. Temporospatial expression of vascular endothelial growth factor and basic fibroblast growth factor during mandibular distraction osteogenesis. Journal of Cranio-Maxillo-Facial Surgery 2003;31:238–43. [127] Salim A, Nacamuli RP, Morgan EF, Giaccia AJ, Longaker MT. Transient changes in oxygen tension inhibit osteogenic differentiation and Runx2 expression in osteoblasts. Journal of Biological Chemistry 2004;279:40007–16. [128] Holstein JH, Klein M, Garcia P, Histing T, Culemann U, Pizanis A, et al. Rapamycin affects early fracture healing in mice. British Journal of Pharmacology 2008;154:1055–62. [129] Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, et al. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-

308

[130]

[131]

[132] [133] [134]

[135] [136]

[137]

[138] [139] [140]

[141]

[142]

[143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310 1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. Journal of Biological Chemistry 2004;279:10331–37. Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, Hwang J, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. Journal of Biological Chemistry 2003;278:31128–35. Bouletreau PJ, Warren SM, Spector JA, Peled ZM, Gerrets RP, Greenwald JA, et al. Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plastic and Reconstructive Surgery 2002;109:2384–97. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233–41. Cai J, Pardali E, Sanchez-Duffhues G, ten Dijke P. BMP signaling in vascular diseases. FEBS Letters 2012;586:1993–2002. Horner A, Bord S, Kelsall AW, Coleman N, Compston JE. Tie2 ligands angiopoietin-1 and angiopoietin-2 are coexpressed with vascular endothelial cell growth factor in growing human bone. Bone 2001;28:65–71. Levin ER. Endothelins. New England Journal of Medicine 1995;333:356–63. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–5. Kitten AM, Andrews CJ. Endothelin-1 expression in long-term cultures of fetal rat calvarial osteoblasts: regulation by BMP-7. Journal of Cellular Physiology 2001;187:218–25. Rodriguez-Pascual F, Busnadiego O, Lagares D, Lamas S. Role of endothelin in the cardiovascular system. Pharmacological Research 2011;63:463–72. Knowles J, Loizidou M, Taylor I. Endothelin-1 and angiogenesis in cancer. Current Vascular Pharmacology 2005;3:309–14. Morbidelli L, Orlando C, Maggi CA, Ledda F, Ziche M. Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. American Journal of Physiology 1995;269:H686–95. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A. Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor1alpha in ovarian carcinoma cells. Journal of Biological Chemistry 2002;277: 27850–55. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A. Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion. Journal of Biological Chemistry 2004;279:46700–05. Salani D, Taraboletti G, Rosano L, Di Castro V, Borsotti P, Giavazzi R, et al. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. American Journal of Pathology 2000;157:1703–11. Spinella F, Garrafa E, Di Castro V, Rosano L, Nicotra MR, Caruso A, et al. Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. Cancer Research 2009;69:2669–76. Kozawa O, Kawamura H, Hatakeyama D, Matsuno H, Uematsu T. Endothelin1 induces vascular endothelial growth factor synthesis in osteoblasts: involvement of p38 mitogen-activated protein kinase. Cellular Signalling 2000;12:375–80. Veillette CJ, von Schroeder HP. Endothelin-1 down-regulates the expression of vascular endothelial growth factor-A associated with osteoprogenitor proliferation and differentiation. Bone 2004;34:288–96. Qu G, von Schroeder HP. Role of osterix in endothelin-1-induced downregulation of vascular endothelial growth factor in osteoblastic cells. Bone 2006;38:21–9. Kitano Y, Kurihara H, Kurihara Y, Maemura K, Ryo Y, Yazaki Y, et al. Gene expression of bone matrix proteins and endothelin receptors in endothelin1-deficient mice revealed by in situ hybridization. Journal of Bone and Mineral Research 1998;13:237–44. von Schroeder HP, Veillette CJ, Payandeh J, Qureshi A, Heersche JN. Endothelin-1 promotes osteoprogenitor proliferation and differentiation in fetal rat calvarial cell cultures. Bone 2003;33:673–84. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proceedings of the National Academy of Sciences of the United States of America 1998;95: 3597–602. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165–76. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proceedings of the National Academy of Sciences of the United States of America 1990;87:7260–4. Kim HH, Shin HS, Kwak HJ, Ahn KY, Kim JH, Lee HJ, et al. RANKL regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. FASEB Journal 2003;17:2163–5. Kim YM, Lee YM, Kim HS, Kim JD, Choi Y, Kim KW, et al. TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. Journal of Biological Chemistry 2002;277:6799–805. Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arteriosclerosis Thrombosis and Vascular Biology 2002;22:549–53.

[156] Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factorkappaB ligand and osteoprotegerin in bone cell biology. Journal of Molecular Medicine 2001;79:243–53. [157] Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circulation Research 2004;95:1046–57. [158] Sattler AM, Schoppet M, Schaefer JR, Hofbauer LC. Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease. Calcified Tissue International 2004;74:103–6. [159] Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. Journal of Biological Chemistry 2000;275:20959–62. [160] Pritzker LB, Scatena M, Giachelli CM. The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival. Molecular Biology of the Cell 2004;15:2834–41. [161] Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K, et al. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochemical and Biophysical Research Communications 1998;246:337–41. [162] Nagai M, Sato N. Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation. Biochemical and Biophysical Research Communications 1999;257:719–23. [163] Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. Journal of Experimental Medicine 1998;188:997–1001. [164] Kurata K, Heino TJ, Higaki H, Vaananen HK. Bone marrow cell differentiation induced by mechanically damaged osteocytes in 3D gel-embedded culture. Journal of Bone and Mineral Research 2006;21:616–25. [165] David L, Feige JJ, Bailly S. Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine and Growth Factor Reviews 2009;20:203–12. [166] Wiley DM, Kim JD, Hao J, Hong CC, Bautch VL, Jin SW. Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nature Cell Biology 2011;13:686–92. [167] Rosen V. BMP and BMP inhibitors in bone. Annals of the New York Academy of Sciences 2006;1068:19–25. [168] Ramoshebi LN, Ripamonti U. Osteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor-beta1. Anatomical Record 2000;259:97–107. [169] Yeh LC, Lee JC. Osteogenic protein-1 increases gene expression of vascular endothelial growth factor in primary cultures of fetal rat calvaria cells. Molecular and Cellular Endocrinology 1999;153:113–24. [170] Garimella R, Tague SE, Zhang J, Belibi F, Nahar N, Sun BH, et al. Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling. Journal of Histochemistry and Cytochemistry 2008;56:569–77. [171] Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proceedings of the National Academy of Sciences of the United States of America 2008;105:20764–69. [172] Xiao G, Gopalakrishnan R, Jiang D, Reith E, Benson MD, Franceschi RT. Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. Journal of Bone and Mineral Research 2002;17:101–10. [173] Cohen S. The stimulation of epidermal proliferation by a specific protein (EGF). Developmental Biology 1965;12:394–407. [174] Cohen S, Elliott GA. The stimulation of epidermal keratinization by a protein isolated from the submaxillary gland of the mouse. Journal of Investigative Dermatology 1963;40:1–5. [175] Gospodarowicz D, Bialecki H, Thakral TK. The angiogenic activity of the fibroblast and epidermal growth factor. Experimental Eye Research 1979;28:501–14. [176] Taylor JM, Mitchell WM, Cohen S. Epidermal growth factor. Physical and chemical properties. Journal of Biological Chemistry 1972;247:5928–34. [177] Savage Jr CR, Hash JH, Cohen S. Epidermal growth factor. Location of disulfide bonds. Journal of Biological Chemistry 1973;248:7669–72. [178] Carpenter G, Cohen S. Epidermal growth factor. Journal of Biological Chemistry 1990;265:7709–12. [179] Doolittle RF, Feng DF, Johnson MS. Computer-based characterization of epidermal growth factor precursor. Nature 1984;307:558–60. [180] Appella E, Weber IT, Blasi F. Structure and function of epidermal growth factor-like regions in proteins. FEBS Letters 1988;231:1–4. [181] Cooke RM, Wilkinson AJ, Baron M, Pastore A, Tappin MJ, Campbell ID, et al. The solution structure of human epidermal growth factor. Nature 1987;327: 339–41. [182] Hohenester E, Engel J. Domain structure and organisation in extracellular matrix proteins. Matrix Biology 2002;21:115–28. [183] Sanderson MP, Dempsey PJ, Dunbar AJ. Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors. Growth Factors 2006;24:121–36. [184] Kim HS, Shin HS, Kwak HJ, Cho CH, Lee CO, Koh GY. Betacellulin induces angiogenesis through activation of mitogen-activated protein kinase and phosphatidylinositol 3’-kinase in endothelial cell. FASEB Journal 2003;17: 318–20.

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310 [185] De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D, et al. The role of the EGFR signaling in tumor microenvironment. Journal of Cellular Physiology 2008;214:559–67. [186] Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Experimental Cell Research 2003;284:2–13. [187] Singh AB, Harris RC. Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cellular Signalling 2005;17:1183–93. [188] Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Molecular and Cellular Neurosciences 2000;16:631–48. [189] Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Reviews Neuroscience 2008;9:437–52. [190] Dong J, Opresko LK, Chrisler W, Orr G, Quesenberry RD, Lauffenburger DA, et al. The membrane-anchoring domain of epidermal growth factor receptor ligands dictates their ability to operate in juxtacrine mode. Molecular Biology of the Cell 2005;16:2984–98. [191] Tada H, Sasada R, Kawaguchi Y, Kojima I, Gullick WJ, Salomon DS, et al. Processing and juxtacrine activity of membrane-anchored betacellulin. Journal of Cellular Biochemistry 1999;72:423–34. [192] Inui S, Higashiyama S, Hashimoto K, Higashiyama M, Yoshikawa K, Taniguchi N. Possible role of coexpression of CD9 with membrane-anchored heparinbinding EGF-like growth factor and amphiregulin in cultured human keratinocyte growth. Journal of Cellular Physiology 1997;171:291–8. [193] Xiao ZQ, Majumdar AP. Increased in vitro activation of EGFR by membranebound TGF-alpha from gastric and colonic mucosa of aged rats. Americal Journal of Physiology Gastrointestinal and Liver Physiology 2001;281:G111–6. [194] Xian CJ. Roles of epidermal growth factor family in the regulation of postnatal somatic growth. Endocrine Reviews 2007;28:284–96. [195] Schneider MR, Sibilia M, Erben RG. The EGFR network in bone biology and pathology. Trends in Endocrinology and Metabolism 2009;20:517–24. [196] Schneider MR, Mayer-Roenne B, Dahlhoff M, Proell V, Weber K, Wolf E, et al. High cortical bone mass phenotype in betacellulin transgenic mice is EGFRdependent. Journal of Bone and Mineral Research 2009;24:455–67. [197] Wang K, Yamamoto H, Chin JR, Werb Z, Vu TH. Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment. Journal of Biological Chemistry 2004;279:53848–56. [198] Mehta VB, Besner GE. HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways. Growth Factors 2007;25:253–63. [199] Zhang X, Siclari VA, Lan S, Zhu J, Koyama E, Dupuis HL, et al. The critical role of the epidermal growth factor receptor in endochondral ossification. Journal of Bone and Mineral Research 2011;26:2622–33. [200] Qin L, Tamasi J, Raggatt L, Li X, Feyen JH, Lee DC, et al. Amphiregulin is a novel growth factor involved in normal bone development and in the cellular response to parathyroid hormone stimulation. Journal of Biological Chemistry 2005;280:3974–81. [201] Chim SM, Qin A, Tickner J, Pavlos N, Davey T, Wang H, et al. EGFL6 promotes endothelial cell migration and angiogenesis through the activation of extracellular signal-regulated kinase. Journal of Biological Chemistry 2011;286: 22035–46. [202] Li T, Browne RM, Matthews JB. Immunocytochemical expression of growth factors by odontogenic jaw cysts. Molecular Pathology 1997;50:21–7. [203] Campagnolo L, Leahy A, Chitnis S, Koschnick S, Fitch MJ, Fallon JT, et al. EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. American Journal of Pathology 2005;167:275–84. [204] Birdsall MA, Hopkisson JF, Grant KE, Barlow DH, Mardon HJ. Expression of heparin-binding epidermal growth factor messenger RNA in the human endometrium. Molecular Human Reproduction 1996;2:31–4. [205] Vinals F, Pouyssegur J. Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Molecular and Cellular Biology 2001;21:7218–30. [206] Gomez-Gaviro MV, Scott CE, Sesay AK, Matheu A, Booth S, Galichet C, et al. Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. Proceedings of the National Academy of Sciences of the United States of America 2012;109:1317–22. [207] Neiva KG, Zhang Z, Miyazawa M, Warner KA, Karl E, Nor JE. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 2009;11: 583–93. [208] Rotatori DS, Kerr NC, Raphael B, McLaughlin BJ, Shimizu R, Stern GA, et al. Elevation of transforming growth factor alpha in cat aqueous humor after corneal endothelial injury. Investigative Ophthalmology and Visual Science 1994;35:143–9. [209] Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Research 2006;66:2173–80. [210] Bertrand-Duchesne MP, Grenier D, Gagnon G. Epidermal growth factor released from platelet-rich plasma promotes endothelial cell proliferation in vitro. Journal of Periodontal Research 2010;45:87–93.

309

[211] Joyce NC, Joyce SJ, Powell SM, Meklir B. EGF and PGE2: effects on corneal endothelial cell migration and monolayer spreading during wound repair in vitro. Current Eye Research 1995;14:601–9. [212] Mehta VB, Zhou Y, Radulescu A, Besner GE. HB-EGF stimulates eNOS expression and nitric oxide production and promotes eNOS dependent angiogenesis. Growth Factors 2008;26:301–15. [213] Schneider MR, Antsiferova M, Feldmeyer L, Dahlhoff M, Bugnon P, Hasse S, et al. Betacellulin regulates hair follicle development and hair cycle induction and enhances angiogenesis in wounded skin. Journal of Investigative Dermatology 2008;128:1256–65. [214] Grotendorst GR, Soma Y, Takehara K, Charette M. EGF and TGF-alpha are potent chemoattractants for endothelial cells and EGF-like peptides are present at sites of tissue regeneration. Journal of Cellular Physiology 1989;139:617–23. [215] Schreiber AB, Winkler ME, Derynck R. Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor. Science 1986;232:1250–3. [216] Leker RR, Toth ZE, Shahar T, Cassiani-Ingoni R, Szalayova I, Key S, et al. Transforming growth factor alpha induces angiogenesis and neurogenesis following stroke. Neuroscience 2009;163:233–43. [217] LeJeune S, Leek R, Horak E, Plowman G, Greenall M, Harris AL. Amphiregulin, epidermal growth factor receptor, and estrogen receptor expression in human primary breast cancer. Cancer Research 1993;53:3597–602. [218] Desruisseau S, Palmari J, Giusti C, Romain S, Martin PM, Berthois Y. Clinical relevance of amphiregulin and VEGF in primary breast cancers. International Journal of Cancer 2004;111:733–40. [219] Berasain C, Castillo J, Perugorria MJ, Prieto J, Avila MA. Amphiregulin: a new growth factor in hepatocarcinogenesis. Cancer Letters 2007;254:30–41. [220] Yotsumoto F, Fukami T, Yagi H, Funakoshi A, Yoshizato T, Kuroki M, et al. Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer. Cancer Science 2010;101:2351–60. [221] Ma L, Gauville C, Berthois Y, Millot G, Johnson GR, Calvo F. Antisense expression for amphiregulin suppresses tumorigenicity of a transformed human breast epithelial cell line. Oncogene 1999;18:6513–20. [222] Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circulation Research 2012;111:1376–85. [223] De Maziere A, Parker L, Van Dijk S, Ye W, Klumperman J. Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis. Developmental Dynamics 2008;237: 580–91. [224] Parker LH, Schmidt M, Jin SW, Gray AM, Beis D, Pham T, et al. The endothelialcell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 2004;428:754–8. [225] Schmidt M, Paes K, De Maziere A, Smyczek T, Yang S, Gray A, et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 2007;134:2913–23. [226] Wu F, Yang LY, Li YF, Ou DP, Chen DP, Fan C. Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma. Hepatology 2009;50:1839–50. [227] Schmidt MH, Bicker F, Nikolic I, Meister J, Babuke T, Picuric S, et al. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nature Cell Biology 2009;11:873–80. Dr. Shek Man Chim is a research associate in Molecular Laboratory, School of Pathology and Laboratory Medicine at The University of Western Australia. He received his BSc (Hons) in Biology from the Hong Kong University of Science and Technology in 2004, and PhD from the University of Western Australia in 2009. His research interest is to understand the intercellular communication between bone cells and endothelial cells, which will aid in advancing our knowledge of bone remodeling and angiogenesis, and may facilitate to design novel therapeutic strategies for the treatment of disease. Dr. Jennifer Tickner is a Postdoctoral Research Associate in the Cell Signalling Group, based at the University of Western Australia. She graduated from the University of Western Australia with 1st class honours in microbiology and subsequently obtained her PhD in Anatomy and Developmental Biology from University College London in 2006. Her doctoral work was completed in the research group of Prof. Tim Arnett, studying the effects of oxygen tension on bone cells. She has published several papers on the effects of physiological factors on bone cell formation and activity, and a review on signalling pathways in osteoclasts. She is currently working on phenotypic and mechanistic analysis of ENU-mutagenised mouse models to identify novel regulators of bone homeostasis.

310

S.M. Chim et al. / Cytokine & Growth Factor Reviews 24 (2013) 297–310 Siu To Chow received his BSc in Molecular Medicine and Biochemistry and Master of Infectious Disease in School of Pathology and Laboratory Medicine at the University of Western Australia. He was involved in research projects investigating novel molecules secreted by osteoblasts and osteoclasts which have potential to regulate angiogenesis and bone homeostasis via paracrine/autocrine mechanism.

Vincent Kuek is a PhD student in Molecular Laboratory, School of Pathology and Laboratory Medicine at The University of Western Australia (UWA). He completed his Bsc (Hons) in Microbiology at UWA. His research project focuses on the discovery of genes and their mechanisms involved in the intercellular crosstalk between osteoblasts, osteoclasts and endothelial cells, which may potentially lead to the development of new therapeutic treatments and improved treatments for bone diseases.

Dr. Baosheng Guo is the Postdoctoral Research Fellow of the Hong Kong Baptist University. He was graduated from the Hebei North University, Hebei, China and perused his Bachelor Degree of Medicine in 2005. Then, he began his postgraduate research project of Master Degree at the Shanghai University of Chinese Medicine, Shanghai, China and the Hong Kong Polytechnic University, Hong Kong. He finished his PhD study at Department of Orthopaedics & Traumatology of the Chinese University of Hong Kong in 2012. He previously worked as resident at the Luo Yang Orthopeadic & Traumatology Hospital in 2006 and research assistant at Department of Rehabilitation Sciences of the Hong Kong Polytechnic University, Hong Kong from 2008 to 2009. Dr. Baosheng Guo has the technical expertise on bone biomechanics, bone bioimaging and bone biology and focused research study on muscle atrophy as well as RNAi-based or phytotherapy-based translational research in osteoporosis. Relate research work has been published on PloS One, Nature Medicine and Bone. Prof. Ge Zhang is the associate professor of the Hong Kong Baptist University and the author of over 106 peerreviewed papers on RNAi-based or phytotherapy-based translational research, targeted delivery in osteoporosis, osteonecrosis, osteoarthritis, rheumatoid arthritis and facture repair. He was educated at the Shanghai University of Chinese Medicine, Shanghai, China and got the Doctor Degree of Medicine in 1995. Then, he started his research career at the Institute of Orthopaedics & Traumatology, Shanghai University of Chinese Medicine, China in 1997 and finished his PhD project from 2000 to 2003. Then, he worked as Postdoctoral Research Fellow at Department of Orthopaedics & Traumatology of the Chinese University of Hong Kong from 2004 to 2007. In 2007, he was the Research Assistant Professor of the Chinese University of Hong Kong. In 2012, Prof. Ge Zhang was appointed as Associate Professor of the Hong Kong Baptist University. Prof. Ge Zhang has comprehensive expertise on bone bioimaging, bone biology and bone biomechanics and interested in RNAi-based or phytotherapy-based translational research on joint and musculoskeletal diseases. The research work was published on over 106 peer-reviewed journals, such as Nature Medicine, Arthritis & Rheumatism, Journal of Bone and Mineral Research and Bone.

Prof. Vicki Rosen arrived at Harvard School of Dental Medicine (HSDM) by way of industry, having spent the majority of her research career as a scientist at Genetics Institute, a biotechnology company, where she was part of a research team that identified the bone morphogenetic protein (BMP) genes in 1988. She became a professor in the Faculty of Medicine in 2001, and chair of the Department of Developmental Biology at HSDM in 2005. Prof. Rosen’s lab studies the physiological roles that BMPs play in the development, maintenance, and repair of musculoskeletal tissues (bone, cartilage, tendon, ligament, meniscus, muscle) using molecular, cellular, and genetic approaches in a variety of model systems. Prof. Rosen believes that enhancing our current understanding of BMP biology will lead to the development of novel strategies for repair and regeneration of individual components of the musculoskeletal system, and also will provide new models for examining the complex tissue interactions that are required for its function. Prof. Erber graduated in Medicine with 1st class honours from the University of Sydney. She undertook her Haematology training at the Royal North Shore Hospital of Sydney and the University of Oxford (as a Rhodes Scholar) where she undertook research leading to Doctorate of Philosophy. She has held Haematologist posts at Royal Perth Hospital, PathCentre, and most recently Addenbrooke’s Hospital in Cambridge. She took up her current appointment as Chair and Head of the School of Pathology and Laboratory Medicine at the University of Western Australia in May 2011. Throughout her professional career Prof. Erber’s major interest has been the adoption of new cutting-edge technologies, translating these into diagnostic pathology practice, especially in the field of haematological malignancies. She has more than 140 publications in peer-reviewed journals and published 3 books. Prof. Jiake Xu is Winthrop Professor and Head of Molecular Laboratory in the School of Pathology and Laboratory Medicine at the University of Western Australia (UWA). He is also a founding Fellow, Faculty of Science, the Royal College of Pathologists of Australia, and has been appointed the President-elect of the Australian and New Zealand Orthopaedic Research Society (ANZORS). He finished his medical training in Guangzhou Medical College in China in 1985. After completing his PhD studies at UWA in 1994, he carried out his postdoctoral research at Stanford University from 1994 to 1998. He returned to UWA in 1998, and has since undertaken research and teaching in the Schools of Surgery and Pathology and Laboratory Medicine. His current research activities are focused on gene discovery, molecular mechanisms of osteoclast functions and the intercellular communication between osteoclasts and osteoblasts, which have significant implication in bone diseases; including osteoporosis, Paget’s disease of bone and malignancy-related osteolysis.