DDR2–CYR61–MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes

Abstract

Regulation of matrix metalloproteinases (MMPs) by collagen in the fibroblast-like synoviocytes (FLSs) plays a critical role in joint destruction in rheumatoid arthritis (RA). Our previous study indicated that discoidin receptor 2 (DDR2) mediated collagen upregulation of MMPs. However, the precise underlying mechanism remains unclear. We report here that CYR61, a secreted, extracellular matrix-associated signaling protein which is capable of regulating a broad range of cellular activities, including cell adhesion, migration, proliferation, and apoptosis, is significantly upregulated in collagen II-stimulated RA FLS. Further studies found that collagen II-activated phosphorylated-DDR2 induces CYR61 through activation of transcription factor activator protein 1 (AP-1). The elevated CYR61, in turn, accelerates MMP1 production via ETS1 (ETS proto-oncogene 1). In addition, CYR61 significantly promotes FLS invasion and migration. Blockade of CYR61 by an adenovirus expressing CYR61 shRNA (Ad-shCYR61) in vivo remarkably ameliorated the severity of arthritis, reduced inflammatory cytokine secretion, and attenuated bone erosion as detected by micro-computed tomography (μCT), in collagen-induced arthritis (CIA) rats. Taken together, we uncovered the Collagen II-DDR2-AP-1-CYR61-ETS1-MMP1 loop in RA FLS. In which, CYR61 acts as a hinge to promote cartilage damage through regulating FLS invasion, migration, and MMP1 production and the inflammatory cascade in RA. Thus, CYR61 may be a promising diagnostic and therapeutic target for RA treatment. © 2016 American Society for Bone and Mineral Research.

Linking systemic angiogenic markers to synovial vascularization in rheumatoid arthritis

“…Although we failed to link CYR61 to synovial vascularization in the present study, CYR61 correlated with disease duration and increased CYR61 levels were observed in patients with high disease activity, bone erosions and HAQ>1.5. These findings are consistent with the implication of CYR61 signaling pathway in the development of bone erosion recently described, and the evaluation of CYR61 as a biomarker of structural progression in RA should be further considered [ 46 ].…”

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

“…Furthermore, plenty of activated signaling pathways promote the secretion of inflammatory factors and aggravated immune response [ 18 , 19 ]. Particularly, regulators of extracellular matrix (ECM), such as MMPs [ 20 , 21 ], which enhanced the invasiveness of FLSs, are regarded as the “killer” of joint destruction. However, the activity of MMPs is controlled by TIMPs.…”

Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review)

“…Fibroblasts may suppress the inflammatory response, and may be considered as a novel target for the therapy of inflammation. Huang et al ( 21 ) demonstrated that CCN1/Cyr61 markedly facilitates rheumatoid arthritis (RA) fibroblast-like synoviocyte invasion and migration and may act as a promising therapeutic target for RA treatment. Wei et al ( 22 ) suggested that CCN1/Cyr61 expression is significantly associated with the metastasis of gastric cardia adenocarcinoma (GCA).…”

“…The overexpression of CCN1/Cyr61 activates the nuclear factor (NF)-κB pathway and induces hepatic stellate cell apoptosis through endoplasmic reticulum stress and initiation of the unfolded protein response ( 23 ). Conversely, CCN1/Cyr61 expression promotes kidney tubular epithelial cell proliferation and cell apoptosis is inhibited ( 21 ). The functions of CCN1/Cyr61 in promoting cell survival or inducing apoptosis in different cell-types is important to elucidate its role in tissue reconstruction.…”