Cyr61 Participates In The Pathogenesis Of Rheumaroid Arthritis Via Promoting MMP-3 Expression

Rheumatoid arthritis(RA)is a chronic,immune-regulated inflammatory disease which involves hyperplasia of synovial tissues(ST),excessive inflammatory response and destruction of cartilage,bone and ligaments.Matrix metalloproteinase-3(MMP-3),a family member of zinc metalloendopeptises,secreted by fibroblast-like synoviocytes(FLS),is one of the most important cytokines involved in the erosive changes in cartilage and bone.Cysteine-rich protein 61(Cyr61)/CCN1 is the first cloned member of the CCN family and recently is considered as a novel pro-inflammatory factor.In previous studies,we first reported that the expression of Cyr61 was greatly enhanced in the FLS from RA patients;this increased expression of Cyr61 in turn acts further to stimulate FLS proliferation,induces inflammatory cytokines such as IL-6,IL-8,IL-1? expression,accumulating the pathogenesis of RA.Whether Cyr61 has any effect on the expression of MMP-3 by RA FLS has not yet been reported.In this study,we studied the effect of Cyr61 on the MMP-3 expression in RA FLS.Results showed that the levels of MMP-3 and Cyr61 in RA synovial fluid(SF)and ST are higher than those in OA SF and ST.Moreover,high level of MMP-3 was positively correlated with the expression of Cyr61 in RA ST.In vitro study,we found that Cyr61 stimulated MMP-3 production in a dose dependent manner,blocking of Cyr61 action with a monoclonal antibody(mAb,093G9)or knocking down Cyr61 expression with special siRNA could reduce MMP-3 expression in FLS,and IL-1?,TNF-? were not involved in this process.Results also showed that Cyr61 could enhance the invasive ability of RA FLS via promoting MMP-3 expression.Besides,In vivo study,we found that Collagen induced arthritis(CIA)mice treated with 093G9(Cyr61 monoantibody)showed a lower inflammatory scores and MMP-3 expression in the joints compared with CIA mice treated with con-IgG.Mechanistically,we found that Cyr61 stimulated MMP-3 production via the P38,JNK-dependent AP-1 signaling pathway in FLS from RA patients.In conclusion,Cyr61 plays a critical role in stimulating MMP-3 production by FLS which contribute to the bone erosion pathogenesis of RA.Taken together with the effect of Cyr61 in FLS proliferation and inflammatory cytokines expression,we suggest that targeting of Cyr61 may represent a novel strategy in RA treatment.