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The Matricellular Protein CYR61 Inhibits Osteoclastogenesis by a Mechanism Independent of _vß₃ and _vß₅

Bone and Musculoskeletal Research Programme (J.C.C., D.T., A.D., M.J.R.), Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; and Orthopaedic Institute (N.S., S.J., F.J.), Molecular Orthopaedics, 97074 Wuerzburg, Germany

Address all correspondence and requests for reprints to: Professor Michael J. Rogers, Bone Research Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. E-mail: m.j.rogers{at}abdn.ac.uk.

Cysteine-rich protein 61 (CYR61/CCN1) belongs to the family of CCN matricellular proteins. Most of the known effects of CCN proteins appear to be due to binding to extracellular growth factors or integrins, including _vß₃ and _vß₅. Although CYR61 can stimulate osteoblast differentiation, until now the effect of CYR61 on osteoclasts was unknown. We demonstrate that recombinant human CYR61 inhibits the formation of multinucleated, _vß₃-positive, or tartrate-resistant acid phosphatase-positive human, mouse, and rabbit osteoclasts in vitro. CYR61 markedly reduced the expression of the osteoclast phenotypic markers tartrate-resistant acid phosphatase, matrix metalloproteinase-9, calcitonin receptor, and cathepsin K. However, CYR61 did not affect the formation of multinucleated osteoclasts when added to osteoclast precursors prior to fusion or affect the number or resorptive activity of osteoclasts cultured on dentine discs, indicating that CYR61 affects early osteoclast precursors but not mature osteoclasts. CYR61 did not affect receptor activator of nuclear factor-B (RANK) ligand-induced phosphorylation of p38 or ERK1/2 in human macrophages and did not affect RANK ligand-induced activation of nuclear factor-B, indicating that CYR61 does not appear to inhibit osteoclastogenesis by affecting RANK signaling. Furthermore, a mutant form of CYR61 defective in binding to _vß₃ also inhibited osteoclastogenesis, and CYR61 inhibited osteoclastogenesis similarly in cultures of mouse wild-type or ß₅^–/– macrophages. Thus, CYR61 does not appear to inhibit osteoclast formation by interacting with _vß₃ or _vß₅. These observations demonstrate that CYR61 is a hitherto unrecognized inhibitor of osteoclast formation, although the exact mechanism of inhibition remains to be determined. Given that CYR61 also stimulates osteoblasts, CYR61 could represent an important bifunctional local regulator of bone remodeling.