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

Regulation of matrix metalloproteinases (MMPs) by collagen in the fibroblast-like synoviocytes (FLS) plays a critical role in joint destruction in rheumatoid arthritis (RA). Our previous study indicated that discoidin receptor 2 (DDR2) mediated collagen-up-regulation 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 up-regulated 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. 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-CT, in 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. This article is protected by copyright. All rights reserved