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Mesenchymal stem cell roles in osteoarthritis (joint) disease
Chapter 9
Mesenchymal stem cell roles in osteoarthritis (joint) disease Deming Jiang Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC
Human joints are complex structures that connect adjacent bones to form functional units. A normal and complete unit works like a machine to permit constrained joint motion. Human joints mainly include hip joints, knees, and small joints in the fingers. As shown in Fig. 9.1, common joints are composed of several elements, including two articulating bones, the articular cartilage, the synovial membrane, and the tendons, ligaments, and menisci (in knee joints; Goldring and Goldring, 2016). The cartilage is the most important part in a joint. It is usually separated from subchondral bones by a thin layer of calcified cartilage that persists after growth plate closure. The osteochondral unit in a joint is the functional part formed by the articular cartilage and subchondral bone. The calcified articular cartilage has the capability of transferring loads and reducing friction during weight bearing and joint motion. In daily life, joints stay in a steady state. Any alteration in this system results in the disruption of joint integrity and loss of function, contributing to osteoarthritis (OA). OA is the most prevalent chronic disease worldwide, seriously affecting the life quality of individuals and populations (Bortoluzzi et al., 2018). OA is a degenerative joint disease with a global prevalence in the knee of 3.8% and in the hip of 0.85%, based on a Global Burden of Disease study (Cross et al., 2014). The main pathological feature of OA is the progressive breakdown of articular cartilage and underlying bone (Fig. 9.2). Symptoms commonly occur after exercise in the beginning, gradually becoming constant. Other features, such as osteophyte formation, increase in subchondral bone mass, synovial tissue inflammation, and hyperplasia, are also identified (Liao et al., 2017). The pathogenesis of OA is due to a joint action of chemical, physical, and mechanical factors, resulting in cartilage matrix damage; however, the process is complex and internal mechanisms are still ambiguous. During progression, collagen networks break down, and the glycosaminoglycan in the network starts Mesenchymal Stem Cells in Human Health and Diseases. https://doi.org/10.1016/B978-0-12-819713-4.00009-8 Copyright © 2020 Elsevier Inc. All rights reserved.
161
162 Mesenchymal Stem Cells in Human Health and Diseases
FIGURE 9.1 Schematic diagrams of human joints.
FIGURE 9.2 Schematic comparison between healthy knee and arthritic knee.
to degrade. The water content in the cartilage was also shown to increase, signifying the loss of negatively charged glycosaminoglycan, ultimately resulting in matrix swelling. In addition, the proliferating chondrocytes release a variety of enzymes (matrix metalloproteinases, collagenase, etc.), which accelerates degradation of the cartilage matrix. This effect subsequently initiates a vicious cycle where the body responds by speeding up the synthesis of new matrix to repair the damaged cartilage. However, it usually conversely exacerbates the condition, such as by the progressive loss of articular cartilage. An anatomist in 1743, named William Hunter, said: “. from Hippocrates down to the present age, we shall find, that an ulcerated cartilage is universally allowed to be a troublesome disease . and that, when destroyed, it is never recovered.” Articular cartilage defect is the major pathological feature of OA, and is mainly composed of chondrocytes and collagen type II. Due to the lack
Mesenchymal stem cell roles in osteoarthritis (joint) disease Chapter | 9
163
of blood supply, the articular cartilage has insufficient ability to heal itself once damaged; in the absence of prompt treatment, the cartilage damage will gradually deteriorate and progress to OA. When cartilage is damaged, the body will try to regenerate damaged parts through the formation of fibrocartilage to fill in defects. Fibrocartilage comprises both collagen types I and II, different from native articular hyaline cartilage, which contains only collagen type II. Thus, the repaired structure will be different from the healthy hyaline cartilage in terms of structure. The formation of fibrocartilage leads to worse mechanical function of the joint. OA is recognized as a complex chronic degenerative joint disease that may be caused by mechanical damage, metabolic disturbance, endocrine disorder, or even obesity; however, the complete set of pathogenic factors of OA has yet to be identified. What is identified is that the potency of stem cells to differentiate into multiple lineages becomes more limited as people age; however, there are subpopulations of stem cells residing in the quiescent state that can reenter the cell cycle when they are activated, expressing partial differentiation potential (Morrison et al., 1997). The existence of stem/progenitor cells has been identified in specific tissues and they may be involved in tissue homeostasis maintenance (Miyajima et al., 2014). For example, red blood cells can remain alive for only 100e120 days before they need to be replenished by lineagecommitted stem cells. As for articular cartilage damage, bone marrowe derived mesenchymal stem cells (BMSCs) demonstrate a high potential for repair due to their chondrogenic potential and chondroprotective ability. Because of the capacity of BMSCs to differentiate into chondrocytes, the microfracture technique has been clinically developed for treatment of defective cartilage, aiming to mobilize BMSCs toward the damaged area from the bone marrow. Unfortunately, neither translation of the perichondrium nor the microfracture procedure was shown to be effective for cartilage treatment, possibly due to the lack of vasculature in the articular cartilage. In 2016, some researchers discovered that there is a population of stem/ progenitor cells residing in articular cartilage, which were thought to contribute to the maintenance of cartilage homeostasis (Jiang et al., 2016). Researchers have discovered, isolated, and characterized these cartilagederived stem/progenitor cells, or CSPCs, in human, equine, and bovine articular cartilage; these cells express stem cellerelated markers, and have the capacity to self-renew and differentiate into multiple lineages. However, once isolated for culture, chondrocytes will start to dedifferentiate, gradually losing stem cellerelated markers and the ability to produce cartilaginous extracellular matrix (ECM). In 2003, Barbero et al. found a colony-forming population in differentiated articular cartilage (Barbero et al., 2003). Shortly after, Alsalameh et al. reported a cluster of mesenchymal progenitor cells in normal and osteoarthritic humans with the capability to differentiate into adipocytes and osteocytes (Alsalameh et al., 2004). Moreover, Koelling et al. identified a unique progenitor cell population residing in repaired tissue of articular
164 Mesenchymal Stem Cells in Human Health and Diseases
cartilage during the late stage of OA (Koelling et al., 2009). They found that these cells displayed stem cell behaviors such as multipotency, clonogenicity, and migratory activity and termed them as chondrogenic progenitor cells. It was also reported that chondrogenic progenitor cells isolated from disease tissues have high chondrogenic potential ex vivo. One of the most interesting observations was reported by Seol et al. They found that injuries leading to the death of chondrocytes could stimulate the homing of chondrogenic progenitor cells, inducing repopulation of matrix and repair of chondral damage (Seol et al., 2012). Although the origin of CSPCs has not been precisely defined due to the lack of stable surface markers, studies stated that a population of stem/progenitor-like cells had been detected, which mainly existed in the superficial area of mature articular cartilage. The articular cartilage could be classified into three zones: the superficial zone, the middle zone, and the deep zone (Fig. 9.3). The superficial zone has two or three layers, which consist of small, flattened chondrocytes arranged in parallel with the proteoglycan lubricant-producing surface. The middle zone and the deep zone are similar in structure, but chondrocytes in the middle zone are spherical, whereas in the deep zone chondrocytes are enlarged and form columns perpendicular to the joint surface (Jiang and Tuan, 2014). The early OA symptoms can be characterized by changes in the structure of cartilage. Degradation of the superficial zone is the major change. Structural alterations in the internal matrix, such as formation of cell clusters, increase in cell number, and cell embedment within the ECM, are also identified. CSPCs are mainly active at the early stage, aiming to enhance joint resurfacing, ECM production, and chondroprotection. Briefly, CSPCs would first recruit cells responsible for lubricin production, such as proteoglycan 4, to generate a new surface layer to replace the degenerated tissues. CSPCs also stimulate signaling molecules, including transforming growth factor b and bone morphogenetic proteins, shown to be effective in enhancing chondrocyte redifferentiation and ECM remolding. Furthermore, CSPCs inhibit matrix-
FIGURE 9.3 Zone structure of cartilage and cartilage-derived stem/progenitor cell (CSPC) distribution.
Mesenchymal stem cell roles in osteoarthritis (joint) disease Chapter | 9
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degrading enzymes, thus promoting the intrinsic chondroprotective ability of these cells (Jiang and Tuan, 2014). Synovial fluid is a viscous, non-Newtonian fluid found in the cavities of synovial joints. During movement, the synovial fluid plays an important role to reduce friction between the articular cartilages. Synovial tissue is sterile and composed of vascularized connective tissue that lacks a basement membrane. Synovial fluid contains abundant hyaluronic acid and exhibits a tropism for articular cartilage cells. When joints move, synovial fluid flows and brings oxygen and nutrition to the cartilage surface. It is noteworthy that there is a new theory claiming that stem cells exhibiting similar characteristics to MSCs exist in the synovial fluid, termed SF MSCs; these cells were reported to be involved in the hemostasis and reparation of articular cartilage surface. In 2000, Jay et al. observed that human synovial fibroblasts exhibited the same protein, lubricin, as cartilage chondrocytes (Jay et al., 2000, 2010). Lubricin is mainly presented on the surface of the articular cartilage and therefore plays a major role in joint lubrication, protecting joints from load-bearing-induced injuries. Similarly, Jones et al. (Jones et al., 2008) identified SF MSCs in normal human joints and OA patients; he proved that these cells exhibited multilineage differentiation potential, and considerably more clonogenic and less adipogenic potential compared with BMSCs, suggesting that SF MSCs may be more suitable for articular cartilage repair. Another interesting phenomenon, observed by Jones, was that SF MSCs in early OA increased by sevenfold, confirming his previous hypothesis that SF MSCs could be used as a potential treatment for early stage OA. In addition, Caldwell and Wang, 2015 verified that cells residing on the surface of the articular cartilage exhibited gene expression similar to that of stem cells from synovial fluid. Nevertheless, not many studies on SF MSCs have been reported as of this writing; most investigators focus on the application of BMSCs and induced pluripotent stem cells for OA treatment. In 2014, Hatsushika et al. used the knees of pigs that suffered medial meniscal resections as a model. They injected SF MSCs into the knees and observed that the repair process in these treated pigs was significantly better compared with the control group on MRI and histology analyses. Strikingly, in the treated group the cartilage showed better regeneration, and new synovial tissue filled the area of meniscal resection within 2 weeks (Hatsushika et al., 2014). SF MSCs could promote the articular cartilage repair process, mainly through differentiation into chondrocytes and their high expression of collagen type II. Because SF MSCs were identified as extremely chondrogenic, these cells can migrate to the cartilage surface to repair the damage. Moreover, SF MSCs may help recruit MSCs from the bone marrow of the subchondral bone. Endres et al. (2007) investigated that synovial fluid from healthy donors and OA patients showed similar potential to stimulate MSC migration, further confirming the ability of SF MSCs in recruiting BMSCs for repair. In addition,
166 Mesenchymal Stem Cells in Human Health and Diseases
OA is known to be associated with inflammation, with an increasing number of patients suffering from severe inflammation. Previously, it was assumed that inflammation was present only in rheumatoid arthritis patients; however, more studies are now being shifted toward inflammation in OA, with multiple research groups attempting to find an effective approach to treat OA and repair damaged articular cartilage. Due to their antiinflammatory ability, MSCs and SF MSCs have gained a continuously increasing interest as a possible therapeutic option (Ozeki et al., 2016).
Conclusion In summary, the epidemiology, pathology, and treatment of OA have been discussed. We draw a conclusion that OA, referring to articular cartilage damage, could be treated in modern medical conditions. Stem/progenitor cells residing in the cartilage’s superficial zone and the synovial fluid exhibit promising potential for cartilage regeneration, as both can be easily acquired and applied. We also demonstrated that OA development is associated with inflammation, revealing a new avenue toward OA treatment. With antiinflammation effects and better chondrogenic potential compared with normal MSCs, such as BMSCs, synovial fluidederived stem cells are projected for OA treatment and articular cartilage reparation. We believe that with the pace of advancement in stem cells and regenerative medicine, OA could be cured, along with improvement in the quality of life.
References Alsalameh, S., Amin, R., Gemba, T., et al., 2004. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 50 (5), 1522e1532. Barbero, A., Ploegert, S., Heberer, M., et al., 2003. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48 (5), 1315e1325. Bortoluzzi, A., Furini, F., Scire`, C.A., 2018. Osteoarthritis and its management-epidemiology, nutritional aspects and environmental factors. Autoimmunity reviews. Caldwell, K.L., Wang, J., 2015. Cell-based articular cartilage repair: the Link between development and regeneration. Osteoarthr. Cartil. 23 (3), 351e362. Cross, M., Smith, E., Hoy, D., et al., 2014. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73 (7), 1323e1330. Endres, M., Neumann, K.T., Erggelet, C., et al., 2007. Synovial fluid recruits human mesenchymal progenitors from subchondral spongious bone marrow. J. Orthop. Res. 25 (10), 1299e1307. Goldring, S.R., Goldring, M.B., 2016. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat. Rev. Rheumatol. 12 (11), 632e644. Hatsushika, D., Muneta, T., Nakamura, T., et al., 2014. Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model. Osteoarthr. Cartil. 22 (7), 941e950. Jay, G.D., Britt, D.E., Cha, C.J., 2000. Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. J. Rheumatol. 27 (3), 594e600.
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Jay, G.D., Tantravahi, U., Britt, D.E., et al., 2010. Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. J. Orthop. Res. 19 (4), 677e687. Jiang, Y., Cai, Y., Zhang, W., et al., 2016. Human Cartilage-Derived progenitor cells from committed chondrocytes for efficient cartilage repair and regeneration. Stem Cells Transl. Med. 5 (6), 733e744. Jiang, Y., Tuan, R.S., 2014. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat. Rev. Rheumatol. 11, 206e212. Jones, E.A., Crawford, A., English, A., et al., 2008. Synovial fluid mesenchymal stem cells in health and early osteoarthritis: Detection and functional evaluation at the single-cell level. Arthritis Rheum. 58 (6), 1731e1740. Koelling, S., Kruegel, J., Irmer, M., et al., 2009. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell 4 (4), 324e335. Liao, L., Zhang, S., Gu, J., et al., 2017. Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-Induced osteoarthritis in adult MICE. Sci. Rep. 7 (1), 2371e2383. Miyajima, A., Tanaka, M., Itoh, T., 2014. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14 (5), 561e574. Morrison, S.J., Shah, N.M., Anderson, D.J., 1997. Regulatory mechanisms in stem cell biology. Cell 88 (3), 287e298. Ozeki, N., Muneta, T., Koga, H., et al., 2016. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthritis Cartilage 24 (6), 1061e1070. Seol, D., Mccabe, J.D., Choe, H., et al., 2012. Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum. 64 (11), 3626e3637.
Further reading Alessandra, B., Federica, F., Scire`, C.A., 2018. Osteoarthritis and its management e epidemiology, nutritional aspects and environmental factors. Autoimmun. Rev. 17 (11), 1097e1104. Andrea, B., Sabine, P., Michael, H., et al., 2010. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48 (5), 1315e1325. Atsushi, M., Minoru, T., Tohru, I., 2014. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14 (5), 561e574. Jiang, Y., Tuan, R.R., 2015. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat. Rev. Rheumatol. 11 (4), 206e212. Marita, C., Emma, S., Damian, H., et al., 2014. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73 (7), 1323e1330. Saifeddin, A., Rayya, A., Takefumi, G., et al., 2010. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheumatol. 50 (5), 1522e1532.
Mesenchymal stem cell roles in osteoarthritis (joint) disease Deming Jiang Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC
Human joints are complex structures that connect adjacent bones to form functional units. A normal and complete unit works like a machine to permit constrained joint motion. Human joints mainly include hip joints, knees, and small joints in the fingers. As shown in Fig. 9.1, common joints are composed of several elements, including two articulating bones, the articular cartilage, the synovial membrane, and the tendons, ligaments, and menisci (in knee joints; Goldring and Goldring, 2016). The cartilage is the most important part in a joint. It is usually separated from subchondral bones by a thin layer of calcified cartilage that persists after growth plate closure. The osteochondral unit in a joint is the functional part formed by the articular cartilage and subchondral bone. The calcified articular cartilage has the capability of transferring loads and reducing friction during weight bearing and joint motion. In daily life, joints stay in a steady state. Any alteration in this system results in the disruption of joint integrity and loss of function, contributing to osteoarthritis (OA). OA is the most prevalent chronic disease worldwide, seriously affecting the life quality of individuals and populations (Bortoluzzi et al., 2018). OA is a degenerative joint disease with a global prevalence in the knee of 3.8% and in the hip of 0.85%, based on a Global Burden of Disease study (Cross et al., 2014). The main pathological feature of OA is the progressive breakdown of articular cartilage and underlying bone (Fig. 9.2). Symptoms commonly occur after exercise in the beginning, gradually becoming constant. Other features, such as osteophyte formation, increase in subchondral bone mass, synovial tissue inflammation, and hyperplasia, are also identified (Liao et al., 2017). The pathogenesis of OA is due to a joint action of chemical, physical, and mechanical factors, resulting in cartilage matrix damage; however, the process is complex and internal mechanisms are still ambiguous. During progression, collagen networks break down, and the glycosaminoglycan in the network starts Mesenchymal Stem Cells in Human Health and Diseases. https://doi.org/10.1016/B978-0-12-819713-4.00009-8 Copyright © 2020 Elsevier Inc. All rights reserved.
161
162 Mesenchymal Stem Cells in Human Health and Diseases
FIGURE 9.1 Schematic diagrams of human joints.
FIGURE 9.2 Schematic comparison between healthy knee and arthritic knee.
to degrade. The water content in the cartilage was also shown to increase, signifying the loss of negatively charged glycosaminoglycan, ultimately resulting in matrix swelling. In addition, the proliferating chondrocytes release a variety of enzymes (matrix metalloproteinases, collagenase, etc.), which accelerates degradation of the cartilage matrix. This effect subsequently initiates a vicious cycle where the body responds by speeding up the synthesis of new matrix to repair the damaged cartilage. However, it usually conversely exacerbates the condition, such as by the progressive loss of articular cartilage. An anatomist in 1743, named William Hunter, said: “. from Hippocrates down to the present age, we shall find, that an ulcerated cartilage is universally allowed to be a troublesome disease . and that, when destroyed, it is never recovered.” Articular cartilage defect is the major pathological feature of OA, and is mainly composed of chondrocytes and collagen type II. Due to the lack
Mesenchymal stem cell roles in osteoarthritis (joint) disease Chapter | 9
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of blood supply, the articular cartilage has insufficient ability to heal itself once damaged; in the absence of prompt treatment, the cartilage damage will gradually deteriorate and progress to OA. When cartilage is damaged, the body will try to regenerate damaged parts through the formation of fibrocartilage to fill in defects. Fibrocartilage comprises both collagen types I and II, different from native articular hyaline cartilage, which contains only collagen type II. Thus, the repaired structure will be different from the healthy hyaline cartilage in terms of structure. The formation of fibrocartilage leads to worse mechanical function of the joint. OA is recognized as a complex chronic degenerative joint disease that may be caused by mechanical damage, metabolic disturbance, endocrine disorder, or even obesity; however, the complete set of pathogenic factors of OA has yet to be identified. What is identified is that the potency of stem cells to differentiate into multiple lineages becomes more limited as people age; however, there are subpopulations of stem cells residing in the quiescent state that can reenter the cell cycle when they are activated, expressing partial differentiation potential (Morrison et al., 1997). The existence of stem/progenitor cells has been identified in specific tissues and they may be involved in tissue homeostasis maintenance (Miyajima et al., 2014). For example, red blood cells can remain alive for only 100e120 days before they need to be replenished by lineagecommitted stem cells. As for articular cartilage damage, bone marrowe derived mesenchymal stem cells (BMSCs) demonstrate a high potential for repair due to their chondrogenic potential and chondroprotective ability. Because of the capacity of BMSCs to differentiate into chondrocytes, the microfracture technique has been clinically developed for treatment of defective cartilage, aiming to mobilize BMSCs toward the damaged area from the bone marrow. Unfortunately, neither translation of the perichondrium nor the microfracture procedure was shown to be effective for cartilage treatment, possibly due to the lack of vasculature in the articular cartilage. In 2016, some researchers discovered that there is a population of stem/ progenitor cells residing in articular cartilage, which were thought to contribute to the maintenance of cartilage homeostasis (Jiang et al., 2016). Researchers have discovered, isolated, and characterized these cartilagederived stem/progenitor cells, or CSPCs, in human, equine, and bovine articular cartilage; these cells express stem cellerelated markers, and have the capacity to self-renew and differentiate into multiple lineages. However, once isolated for culture, chondrocytes will start to dedifferentiate, gradually losing stem cellerelated markers and the ability to produce cartilaginous extracellular matrix (ECM). In 2003, Barbero et al. found a colony-forming population in differentiated articular cartilage (Barbero et al., 2003). Shortly after, Alsalameh et al. reported a cluster of mesenchymal progenitor cells in normal and osteoarthritic humans with the capability to differentiate into adipocytes and osteocytes (Alsalameh et al., 2004). Moreover, Koelling et al. identified a unique progenitor cell population residing in repaired tissue of articular
164 Mesenchymal Stem Cells in Human Health and Diseases
cartilage during the late stage of OA (Koelling et al., 2009). They found that these cells displayed stem cell behaviors such as multipotency, clonogenicity, and migratory activity and termed them as chondrogenic progenitor cells. It was also reported that chondrogenic progenitor cells isolated from disease tissues have high chondrogenic potential ex vivo. One of the most interesting observations was reported by Seol et al. They found that injuries leading to the death of chondrocytes could stimulate the homing of chondrogenic progenitor cells, inducing repopulation of matrix and repair of chondral damage (Seol et al., 2012). Although the origin of CSPCs has not been precisely defined due to the lack of stable surface markers, studies stated that a population of stem/progenitor-like cells had been detected, which mainly existed in the superficial area of mature articular cartilage. The articular cartilage could be classified into three zones: the superficial zone, the middle zone, and the deep zone (Fig. 9.3). The superficial zone has two or three layers, which consist of small, flattened chondrocytes arranged in parallel with the proteoglycan lubricant-producing surface. The middle zone and the deep zone are similar in structure, but chondrocytes in the middle zone are spherical, whereas in the deep zone chondrocytes are enlarged and form columns perpendicular to the joint surface (Jiang and Tuan, 2014). The early OA symptoms can be characterized by changes in the structure of cartilage. Degradation of the superficial zone is the major change. Structural alterations in the internal matrix, such as formation of cell clusters, increase in cell number, and cell embedment within the ECM, are also identified. CSPCs are mainly active at the early stage, aiming to enhance joint resurfacing, ECM production, and chondroprotection. Briefly, CSPCs would first recruit cells responsible for lubricin production, such as proteoglycan 4, to generate a new surface layer to replace the degenerated tissues. CSPCs also stimulate signaling molecules, including transforming growth factor b and bone morphogenetic proteins, shown to be effective in enhancing chondrocyte redifferentiation and ECM remolding. Furthermore, CSPCs inhibit matrix-
FIGURE 9.3 Zone structure of cartilage and cartilage-derived stem/progenitor cell (CSPC) distribution.
Mesenchymal stem cell roles in osteoarthritis (joint) disease Chapter | 9
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degrading enzymes, thus promoting the intrinsic chondroprotective ability of these cells (Jiang and Tuan, 2014). Synovial fluid is a viscous, non-Newtonian fluid found in the cavities of synovial joints. During movement, the synovial fluid plays an important role to reduce friction between the articular cartilages. Synovial tissue is sterile and composed of vascularized connective tissue that lacks a basement membrane. Synovial fluid contains abundant hyaluronic acid and exhibits a tropism for articular cartilage cells. When joints move, synovial fluid flows and brings oxygen and nutrition to the cartilage surface. It is noteworthy that there is a new theory claiming that stem cells exhibiting similar characteristics to MSCs exist in the synovial fluid, termed SF MSCs; these cells were reported to be involved in the hemostasis and reparation of articular cartilage surface. In 2000, Jay et al. observed that human synovial fibroblasts exhibited the same protein, lubricin, as cartilage chondrocytes (Jay et al., 2000, 2010). Lubricin is mainly presented on the surface of the articular cartilage and therefore plays a major role in joint lubrication, protecting joints from load-bearing-induced injuries. Similarly, Jones et al. (Jones et al., 2008) identified SF MSCs in normal human joints and OA patients; he proved that these cells exhibited multilineage differentiation potential, and considerably more clonogenic and less adipogenic potential compared with BMSCs, suggesting that SF MSCs may be more suitable for articular cartilage repair. Another interesting phenomenon, observed by Jones, was that SF MSCs in early OA increased by sevenfold, confirming his previous hypothesis that SF MSCs could be used as a potential treatment for early stage OA. In addition, Caldwell and Wang, 2015 verified that cells residing on the surface of the articular cartilage exhibited gene expression similar to that of stem cells from synovial fluid. Nevertheless, not many studies on SF MSCs have been reported as of this writing; most investigators focus on the application of BMSCs and induced pluripotent stem cells for OA treatment. In 2014, Hatsushika et al. used the knees of pigs that suffered medial meniscal resections as a model. They injected SF MSCs into the knees and observed that the repair process in these treated pigs was significantly better compared with the control group on MRI and histology analyses. Strikingly, in the treated group the cartilage showed better regeneration, and new synovial tissue filled the area of meniscal resection within 2 weeks (Hatsushika et al., 2014). SF MSCs could promote the articular cartilage repair process, mainly through differentiation into chondrocytes and their high expression of collagen type II. Because SF MSCs were identified as extremely chondrogenic, these cells can migrate to the cartilage surface to repair the damage. Moreover, SF MSCs may help recruit MSCs from the bone marrow of the subchondral bone. Endres et al. (2007) investigated that synovial fluid from healthy donors and OA patients showed similar potential to stimulate MSC migration, further confirming the ability of SF MSCs in recruiting BMSCs for repair. In addition,
166 Mesenchymal Stem Cells in Human Health and Diseases
OA is known to be associated with inflammation, with an increasing number of patients suffering from severe inflammation. Previously, it was assumed that inflammation was present only in rheumatoid arthritis patients; however, more studies are now being shifted toward inflammation in OA, with multiple research groups attempting to find an effective approach to treat OA and repair damaged articular cartilage. Due to their antiinflammatory ability, MSCs and SF MSCs have gained a continuously increasing interest as a possible therapeutic option (Ozeki et al., 2016).
Conclusion In summary, the epidemiology, pathology, and treatment of OA have been discussed. We draw a conclusion that OA, referring to articular cartilage damage, could be treated in modern medical conditions. Stem/progenitor cells residing in the cartilage’s superficial zone and the synovial fluid exhibit promising potential for cartilage regeneration, as both can be easily acquired and applied. We also demonstrated that OA development is associated with inflammation, revealing a new avenue toward OA treatment. With antiinflammation effects and better chondrogenic potential compared with normal MSCs, such as BMSCs, synovial fluidederived stem cells are projected for OA treatment and articular cartilage reparation. We believe that with the pace of advancement in stem cells and regenerative medicine, OA could be cured, along with improvement in the quality of life.
References Alsalameh, S., Amin, R., Gemba, T., et al., 2004. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 50 (5), 1522e1532. Barbero, A., Ploegert, S., Heberer, M., et al., 2003. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48 (5), 1315e1325. Bortoluzzi, A., Furini, F., Scire`, C.A., 2018. Osteoarthritis and its management-epidemiology, nutritional aspects and environmental factors. Autoimmunity reviews. Caldwell, K.L., Wang, J., 2015. Cell-based articular cartilage repair: the Link between development and regeneration. Osteoarthr. Cartil. 23 (3), 351e362. Cross, M., Smith, E., Hoy, D., et al., 2014. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73 (7), 1323e1330. Endres, M., Neumann, K.T., Erggelet, C., et al., 2007. Synovial fluid recruits human mesenchymal progenitors from subchondral spongious bone marrow. J. Orthop. Res. 25 (10), 1299e1307. Goldring, S.R., Goldring, M.B., 2016. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat. Rev. Rheumatol. 12 (11), 632e644. Hatsushika, D., Muneta, T., Nakamura, T., et al., 2014. Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model. Osteoarthr. Cartil. 22 (7), 941e950. Jay, G.D., Britt, D.E., Cha, C.J., 2000. Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. J. Rheumatol. 27 (3), 594e600.
Mesenchymal stem cell roles in osteoarthritis (joint) disease Chapter | 9
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Jay, G.D., Tantravahi, U., Britt, D.E., et al., 2010. Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. J. Orthop. Res. 19 (4), 677e687. Jiang, Y., Cai, Y., Zhang, W., et al., 2016. Human Cartilage-Derived progenitor cells from committed chondrocytes for efficient cartilage repair and regeneration. Stem Cells Transl. Med. 5 (6), 733e744. Jiang, Y., Tuan, R.S., 2014. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat. Rev. Rheumatol. 11, 206e212. Jones, E.A., Crawford, A., English, A., et al., 2008. Synovial fluid mesenchymal stem cells in health and early osteoarthritis: Detection and functional evaluation at the single-cell level. Arthritis Rheum. 58 (6), 1731e1740. Koelling, S., Kruegel, J., Irmer, M., et al., 2009. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell 4 (4), 324e335. Liao, L., Zhang, S., Gu, J., et al., 2017. Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-Induced osteoarthritis in adult MICE. Sci. Rep. 7 (1), 2371e2383. Miyajima, A., Tanaka, M., Itoh, T., 2014. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14 (5), 561e574. Morrison, S.J., Shah, N.M., Anderson, D.J., 1997. Regulatory mechanisms in stem cell biology. Cell 88 (3), 287e298. Ozeki, N., Muneta, T., Koga, H., et al., 2016. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthritis Cartilage 24 (6), 1061e1070. Seol, D., Mccabe, J.D., Choe, H., et al., 2012. Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum. 64 (11), 3626e3637.
Further reading Alessandra, B., Federica, F., Scire`, C.A., 2018. Osteoarthritis and its management e epidemiology, nutritional aspects and environmental factors. Autoimmun. Rev. 17 (11), 1097e1104. Andrea, B., Sabine, P., Michael, H., et al., 2010. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48 (5), 1315e1325. Atsushi, M., Minoru, T., Tohru, I., 2014. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14 (5), 561e574. Jiang, Y., Tuan, R.R., 2015. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat. Rev. Rheumatol. 11 (4), 206e212. Marita, C., Emma, S., Damian, H., et al., 2014. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73 (7), 1323e1330. Saifeddin, A., Rayya, A., Takefumi, G., et al., 2010. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheumatol. 50 (5), 1522e1532.