Endochondral Ossification Signals in Cartilage Degradation During Osteoarthritis Progression in Experimental Mouse Models

  • Kawaguchi, Hiroshi (Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo)
  • Received : 2008.01.26
  • Accepted : 2008.01.28
  • Published : 2008.02.29

Abstract

Osteoarthritis (OA), one of the most common skeletal disorders characterized by cartilage degradation and osteophyte formation in joints, is induced by accumulated mechanical stress; however, little is known about the underlying molecular mechanism. Several experimental OA models in mice by producing instability in the knee joints have been developed to apply approaches from mouse genetics. Although proteinases like matrix metalloproteinases and aggrecanases have now been proven to be the principal initiators of OA progression, clinical trials of proteinase inhibitors have not been successful for the treatment, turning the interest of researchers to the upstream signals of proteinase induction. These signals include undegraded and fragmented matrix proteins like type II collagen or fibronection that affects chondrocytes through distinct receptors. Another signal is proinflammatory factors that are produced by chondrocytes and synovial cells; however, recent studies that used mouse OA models in knockout mice did not support that these factors have a role in the central contribution to OA development. Our mouse genetic approaches found that the induction of a transcriptional activator Runx2 in chondrocytes under mechanical stress contributes to the pathogenesis of OA through chondrocyte hypertrophy. In addition, chondrocyte apoptosis has recently been identified as being involved in OA progression. We hereby propose that these endochondral ossification signals may be important for the OA progression, suggesting that the related molecules can clinically be therapeutic targets of this disease.

Keywords

Apoptosis;Cartilage;Chondrocytes;Endochondral Ossification;Hypertrophy;Osteoarthritis

References

  1. Hayami, T., Pickarski, M., Wesolowski, G.A., McLane, J., Bone, A., Destefano, J., Rodan, G.A., and Duong, le T. (2004). The role of subchondral bone remodeling in osteoarthritis, reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 50, 1193-1206 https://doi.org/10.1002/art.20124
  2. Kojima, F., Naraba, H., Miyamoto, S., Beppu, M., Aoki, H., and Kawai, S. (2004). Membrane-associated prostaglandin E synthase- 1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis. Arthritis Res. Ther. 6, R355-365 https://doi.org/10.1186/ar1195
  3. Koshizuka, Y., Yamada, T., Hoshi, K., Ogasawara, T., Chung, U., Kawano, H., Nakamura, Y., Nakamura, K., Ikegawa, S., and Kawaguchi, H. (2003). Cystatin 10, a novel chondrocyte-specific protein, may promote the last steps of the chondrocyte differentiation pathway. J. Biol. Chem. 278, 48259-48266 https://doi.org/10.1074/jbc.M211639200
  4. Kuhn, K., D'Lima, D.D., Hashimoto, S., and Lotz, M. (2004). Cell death in cartilage. Osteoarthritis Cartilage 12, 1-16
  5. Lee, S.W., Lee, H.J., Chung, W.T., Choi, S.M., Rhyu, S.H., Kim, D.K., Kim, K.T., Kim, J.Y., Kim, J.M., and Yoo, Y.H. (2004). TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis. Arthritis Rheum. 50, 534-542 https://doi.org/10.1002/art.20052
  6. Li, Y., Xu, L., and Olsen, B.R. (2007). Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthritis Cartilage 15, 1101-1105 https://doi.org/10.1016/j.joca.2007.04.013
  7. Lorenz, H., Wenz, W., Ivancic, M., Steck, E., and Richter, W. (2005). Early and stable upregulation of collagen type II. collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading. Arthritis Res. Ther. 7, R156-165 https://doi.org/10.1186/ar1471
  8. Manabe, N., Oda, H., Nakamura, K., Kuga, Y., Uchida, S., and Kawaguchi, H. (1999). Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients. Rheumatology (Oxford). 38, 714-720 https://doi.org/10.1093/rheumatology/38.8.714
  9. Okawa. A., Nakamura, I., Goto, S., Moriya, H., Nakamura, Y., and Ikegawa, S. (1998). Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat. Genet. 19, 271-273 https://doi.org/10.1038/956
  10. Pettersen, I., Figenschau, Y., Olsen, E., Bakkelund, W., Smedsröd, B., and Sveinbjörnsson, B. (2002). Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in human articular chondrocytes in vitro. Biochem. Biophys. Res. Commun. 296, 671-676 https://doi.org/10.1016/S0006-291X(02)00916-6
  11. Shimizu, S., Asou, Y., Itoh, S., Chung, U.I., Kawaguchi, H., Shinomiya, K., and Muneta, T. (2007). Prevention of cartilage degradation with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum. 56, 3358-3365 https://doi.org/10.1002/art.22941
  12. Yamakawa, K., Kamekura, S., Kawamura, N., Saegusa, M., Kamei, D., Murakami, M., Kudo, I., Uematsu, S., Akira, S., Chung, U.I., et al. (2008). Association of microsomal prostaglandin E synthase 1 deficiency with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders. Arthritis Rheum. 58, 172-183 https://doi.org/10.1002/art.23158
  13. Jacques, C., Sautet, A., Moldovan, M., Thomas, B., Humbert, L., and Berenbaum, F. (1999). Cyclooxygenase activity in chondrocytes from osteoarthritic and healthy cartilage. Rev. Rhum. Engl. Ed. 66, 701-704
  14. Le Graverand, M.P., Eggerer, J., Vignon, E., Otterness, I.G., Barclay, L., and Hart, D.A. (2002). Assessment of specific mRNA levels in cartilage regions in a lapine model of osteoarthritis. J. Orthop. Res. 20, 535-544 https://doi.org/10.1016/S0736-0266(01)00126-7
  15. Kamekura, S., Hoshi, K., Shimoaka, T., Chung, U., Chikuda, H., Yamada, T., Uchida, M., Ogata, N., Seichi, A., Nakamura, K., et al. (2005). Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13, 632-641 https://doi.org/10.1016/j.joca.2005.03.004
  16. Clements, K.M., Price, J.S., Chambers, M.G., Visco, D.M., Poole, A.R., and Mason, R.M. (2003). Gene deletion of either in-terleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy. Arthritis Rheum. 48, 3452-3463 https://doi.org/10.1002/art.11355
  17. Takeda, S., Bonnamy, J.P., Owen, M.J., Ducy, P., and Karsenty, G. (2001). Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1- deficient mice. Genes Dev. 15, 467-481 https://doi.org/10.1101/gad.845101
  18. Yamada, T., Kawano, H., Koshizuka, Y., Fukuda, T., Yoshimura, K., Kamekura, S., Saito, T., Ikeda, T., Kawasaki, Y., Azuma, Y., et al. (2006). Carminerin contributes to chondrocyte calcification during endochondral ossification. Nat. Med. 12, 665-670 https://doi.org/10.1038/nm1409
  19. Vincenti, M.P. and Brinckerhoff, C.E. (2002). Transcriptional regulation of collagenase (MMP-1. MMP-13) genes in arthritis, integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 4, 157-164 https://doi.org/10.1186/ar401
  20. Xu, L., Peng, H., Wu, D., Hu, K., Goldring, M.B., Olsen, B.R., and Li, Y. (2005). Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J. Biol. Chem. 280, 548-555 https://doi.org/10.1074/jbc.M411036200
  21. Boos, N., Nerlich, A.G., Wiest, I., von der Mark, K., Ganz, R., and Aebi, M. (1999). Immunohistochemical analysis of type-X-collagen expression in osteoarthritis of the hip joint. J. Orthop. Res. 17, 495-502 https://doi.org/10.1002/jor.1100170406
  22. Burrage, P.S. and Brinckerhoff, C.E. (2007). Molecular targets in osteoarthritis: metalloproteinases and their inhibitors. Curr. Drug Targets 8, 293-303 https://doi.org/10.2174/138945007779940098
  23. Glasson, S.S., Blanchet, T.J., and Morris, E.A. (2007). The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061-1069 https://doi.org/10.1016/j.joca.2007.03.006
  24. Glasson, S.S., Askew, R., Sheppard, B., Carito, B., Blanchet, T., Ma, H.L., Flannery, C.R., Peluso, D., Kanki, K., Yang, Z., et al. (2005). Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644-648 https://doi.org/10.1038/nature03369
  25. Glasson, S.S. (2007). In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr. Drug Targets 8, 367-376 https://doi.org/10.2174/138945007779940061
  26. Matyas, J.R., Huang, D., Chung, M., and Adams, M.E. (2002). Regional quantification of cartilage type II collagen and aggrecan messenger RNA in joints with early experimental osteoarthritis. Arthritis Rheum. 46, 1536-1543 https://doi.org/10.1002/art.10331
  27. Pond, M.J. and Nuki, G. (1973). Experimentally-induced osteoarthritis in the dog. Ann. Rheum. Dis. 32, 387-388 https://doi.org/10.1136/ard.32.4.387
  28. Matyas, J.R., Ehlers, P.F., Huang, D., and Adams, M.E. (1999). The early molecular natural history of experimental osteoarthritis. I. Progressive discoordinate expression of aggrecan and type II procollagen messenger RNA in the articular cartilage of adult animals. Arthritis Rheum. 42, 993-1002 https://doi.org/10.1002/1529-0131(199905)42:5<993::AID-ANR19>3.0.CO;2-U
  29. Nagase, H., Visse, R., and Murphy, G. (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 69, 562-573 https://doi.org/10.1016/j.cardiores.2005.12.002
  30. Ueta, C., Iwamoto, M., Kanatani, N., Yoshida, C., Liu, Y., Enomoto-Iwamoto, M., Ohmori, T, Enomoto, H., Nakata, K., Takada, K., et al. (2001). Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J. Cell Biol. 153, 87-100 https://doi.org/10.1083/jcb.153.1.87
  31. Bluteau, G., Gouttenoire, J., Conrozier, T., Mathieu, P., Vignon, E., Richard, M., Herbage, D., and Mallein-Gerin, F. (2002). Differential gene expression analysis in a rabbit model of osteoarthritis induced by anterior cruciate ligament (ACL) section. Biorheology 39, 247-258
  32. Jimenez, M.J., Balbin, M., Lopez, J.M., Alvarez, J., Komori, T., and Lopez-Otin, C. (1999). Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol. Cell. Biol. 19, 4431-4442 https://doi.org/10.1128/MCB.19.6.4431
  33. Little, C.B., Meeker, C.T., Golub, S.B., Lawlor, K.E., Farmer, P.J., Smith, S.M., and Fosang, A.J. (2007). Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J. Clin. Invest. 117, 1627-1636 https://doi.org/10.1172/JCI30765
  34. von der Mark, K., Kirsch, T., Nerlich, A., Kuss, A., Weseloh, G., Gluckert, K., and Stöss, H. (1992). Type X collagen synthesis in human osteoarthritic cartilage. Indication of chondrocyte hypertrophy. Arthritis Rheum. 35, 806-811 https://doi.org/10.1002/art.1780350715
  35. D'Lima, D., Hermida, J., Hashimoto, S., Colwell, C., and Lotz, M. (2006). Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum. 54, 1814-1821 https://doi.org/10.1002/art.21874
  36. Stanton, H., Rogerson, F.M., East, C.J., Golub, S.B., Lawlor, K.E., Meeker, C.T., Little, C.B., Last, K., Farmer, P.J., Campbell, I.K., et al. (2005). ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434, 648-652 https://doi.org/10.1038/nature03417
  37. Xu, L., Peng, H., Glasson, S., Lee, P.L., Hu, K., Ijiri, K., Olsen, B.R., Goldring, M.B., and Li, Y. (2007). Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum. 56, 2663-2673 https://doi.org/10.1002/art.22761
  38. Kamekura, S., Kawasaki, Y., Hoshi, K., Shimoaka, T., Chikuda, H., Maruyama, Z., Komori, T., Sato, S., Takeda, S., Karsenty, G., et al. (2006). Runx2 contributes to pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 54, 2462-2470 https://doi.org/10.1002/art.22041
  39. Sharma, L. and Kapoor, D. (2007). Epidemiology of osteoarthritis. In, Moskowitz R.W. Altman R.D. Hochberg M.C. Buckwalter J.A. Goldberg V.M. editors. In Osteoarthritis, Diagnosis and Medical/ Surgical Management. 4th ed., R.W. Moskowitz, R.D. Altman, M.C. Hochberg, J.A. Buckwalter, and V.M. Goldberg, eds. (Philadelphia, USA: Lippincott Williams & Wilkins), pp. 3-26