Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis

Abstract

Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis1,2, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen–producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4–specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4–deficient mice and syndecan-4–specific antibody–treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.

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Figure 1: Expression of syndecan-4 in human, rat and mouse is upregulated in osteoarthritic chondrocytes and correlates with the progression of the disease.
Figure 2: Deletion of syndecan-4 protects osteoarthritic cartilage from proteoglycan loss that is accompanied by reduced aggrecan neoepitope staining.
Figure 3: Injection of syndecan-4–specific antibodies into osteoarthritic knees of WT mice protects from proteoglycan loss that is accompanied by reduced aggrecan neoepitope staining.
Figure 4: The activation of ADAMTS-5 depends on its direct interaction with syndecan-4 and on syndecan-4–regulated MMP-3 expression and activity.

References

  1. 1

    Glasson, S.S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Stanton, H. et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434, 648–652 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Gao, G. et al. ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol–anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. J. Biol. Chem. 279, 10042–10051 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Brooks, P.M. The burden of musculoskeletal disease–a global perspective. Clin. Rheumatol. 25, 778–781 (2006).

    Article  Google Scholar 

  5. 5

    Poole, A.R. et al. Proteolysis of the collagen fibril in osteoarthritis. Biochem. Soc. Symp. 70, 115–123 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Pattoli, M.A., MacMaster, J.F., Gregor, K.R. & Burke, J.R. Collagen and aggrecan degradation is blocked in interleukin-1–treated cartilage explants by an inhibitor of IκB kinase through suppression of metalloproteinase expression. J. Pharmacol. Exp. Ther. 315, 382–388 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Tortorella, M.D. et al. Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 284, 1664–1666 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Abbaszade, I. et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J. Biol. Chem. 274, 23443–23450 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Bondeson, J., Wainwright, S., Hughes, C. & Caterson, B. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin. Exp. Rheumatol. 26, 139–145 (2008).

    CAS  PubMed  Google Scholar 

  10. 10

    Song, R.H. et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 56, 575–585 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Tortorella, M.D., Liu, R.Q., Burn, T., Newton, R.C. & Arner, E. Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biol. 21, 499–511 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Tortorella, M.D. et al. ADAMTS-4 (aggrecanase-1): N-terminal activation mechanisms. Arch. Biochem. Biophys. 444, 34–44 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Wang, P. et al. Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. J. Biol. Chem. 279, 15434–15440 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Longpré, J.M. et al. Characterization of proADAMTS5 processing by proprotein convertases. Int. J. Biochem. Cell Biol. 41, 1116–1126 (2009).

    Article  Google Scholar 

  15. 15

    Tkachenko, E., Rhodes, J.M. & Simons, M. Syndecans: new kids on the signaling block. Circ. Res. 96, 488–500 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Molténi, A., Modrowski, D., Hott, M. & Marie, P.J. Differential expression of fibroblast growth factor receptor-1, -2, and -3 and syndecan-1, -2, and -4 in neonatal rat mandibular condyle and calvaria during osteogenic differentiation in vitro. Bone 24, 337–347 (1999).

    Article  Google Scholar 

  17. 17

    Cornelison, D.D., Filla, M.S., Stanley, H.M., Rapraeger, A.C. & Olwin, B.B. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev. Biol. 239, 79–94 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Echtermeyer, F. et al. Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J. Clin. Invest. 107, R9–R14 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Lim, S.T., Longley, R.L., Couchman, J.R. & Woods, A. Direct binding of syndecan-4 cytoplasmic domain to the catalytic domain of protein kinase C α (PKC α) increases focal adhesion localization of PKC α. J. Biol. Chem. 278, 13795–13802 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Wilcox-Adelman, S.A., Denhez, F. & Goetinck, P.F. Syndecan-4 modulates focal adhesion kinase phosphorylation. J. Biol. Chem. 277, 32970–32977 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Saoncella, S. et al. Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers. Proc. Natl. Acad. Sci. USA 96, 2805–2810 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Barre, P.E., Redini, F., Boumediene, K., Vielpeau, C. & Pujol, J.P. Semiquantitative reverse transcription-polymerase chain reaction analysis of syndecan-1 and -4 messages in cartilage and cultured chondrocytes from osteoarthritic joints. Osteoarthritis Cartilage 8, 34–43 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Clements, K.M. et al. Gene deletion of either interleukin-1β, interleukin-1β-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 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Glasson, S.S. et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4–knockout mice. Arthritis Rheum. 50, 2547–2558 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Kamekura, S. et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13, 632–641 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Blom, A.B. et al. Crucial role of macrophages in matrix metalloproteinase–mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 56, 147–157 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Mankin, H.J., Dorfman, H., Lippiello, L. & Zarins, A. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J. Bone Joint Surg. Am. 53, 523–537 (1971).

    CAS  Article  Google Scholar 

  28. 28

    Ostergaard, K., Andersen, C.B., Petersen, J., Bendtzen, K. & Salter, D.M. Validity of histopathological grading of articular cartilage from osteoarthritic knee joints. Ann. Rheum. Dis. 58, 208–213 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Pap, G. et al. Development of osteoarthritis in the knee joints of Wistar rats after strenuous running exercise in a running wheel by intracranial self-stimulation. Pathol. Res. Pract. 194, 41–47 (1998).

    CAS  Article  Google Scholar 

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Acknowledgements

We would like to thank A. Forsberg, S. Niehues, S. Ecklebe and K. Reher for technical assistance. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Pa689/7-1 to T.P. and F.E. and Th667/6-1 to G.T. and C.H.), the Collaborative Research Centres (SFB 492; project B18 to R.D. and B19 to T.P.) and Deutsche Arthrosehilfe e.V (p77-a117-Rüther-EP2-fuer1-knie-ko—49k-2006-7 to M.F.).

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F.E. designed and performed all Sdc4−/− experiments and wrote the manuscript; J.B. performed all anti-Sdc4-Ab and Mmp3 inhibition experiments; R.D. performed collagen X stainings and northern blot experiments; I.M. performed the surgical induced osteoarthritis in the mice; K.N. performed syndecan-4–specific antibody injections and the MAPK assays; M.F. provided the human osteoarthritis samples; Y.J.L. and Y.W.S. provided the rat osteoarthritis model; C.H. performed the real-time gene expression experiments; G.T. participated in evaluating the data; and T.P. participated in data analysis, directed the project and wrote the manuscript.

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Correspondence to Frank Echtermeyer or Thomas Pap.

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Echtermeyer, F., Bertrand, J., Dreier, R. et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15, 1072–1076 (2009). https://doi.org/10.1038/nm.1998

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