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 (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.

Huang TL ，Mu N ，Gu JT ，Shu Z ，Zhang K ，Zhao JK ，Zhang C ，Hao Q ，Li WN ，Zhang WQ ，Liu NN ，Zhang Y ，Zhang W ，Xue XC ，Zhang YQ ... -  《-》

PPARγ agonist rosiglitazone inhibits migration and invasion by downregulating Cyr61 in rheumatoid arthritis fibroblast-like synoviocytes.

Kwon EJ ，Park EJ ，Choi S ，Kim SR ，Cho M ，Kim J ... -  《-》

The discoidin domain receptor 2/annexin A2/matrix metalloproteinase 13 loop promotes joint destruction in arthritis through promoting migration and invasion of fibroblast-like synoviocytes.

Discoidin domain receptor 2 (DDR-2)/matrix metalloproteinase (MMP) signaling is an important pathway involved in cartilage destruction in rheumatoid arthritis (RA). However, the molecular mechanisms of this pathway have not been clearly identified. This study was undertaken to screen key molecules involved in this pathway and evaluate their biologic functions in synovium invasion of RA. DDR-2-interacting proteins were examined in vitro by immunoprecipitation and mass spectrometry, and annexin A2 was acquired. The effects of annexin A2 on fibroblast-like synoviocyte (FLS) migration were evaluated using a Transwell invasion assay and an Erasion trace test. In Ddr2(-/-) mice with collagen-induced arthritis (CIA), hematoxylin and eosin (H&E) staining, immunohistochemical analysis, and Western blot analysis were used to assess expression of DDR-2, annexin A2, and MMP-13, as well as synovial hyperplasia. Rats with CIA were treated with lentivirus annexin A2 small interfering RNA (siRNA), and annexin A2 siRNA effects on joint damage were analyzed based upon arthritis index scores and results of micro-computed tomography and H&E staining. The differences between annexin A2 expression in clinical samples from RA and osteoarthritis patients were compared using Western blotting. Annexin 2 was identified for the first time as a DDR-2 binding protein. It may be phosphorylated by phospho-DDR-2, leading to MMP-13 secretion. The annexin A2 phosphorylation level and MMP-13 expression level were decreased and collagen-induced joint damage greatly reduced in Ddr2(-/-) mice. Joint damage in rats with CIA was significantly ameliorated when annexin A2 was down-regulated. Annexin A2 expression and phosphorylation were elevated in human RA synovial tissue. Annexin A2 is a key molecule in the DDR-2/annexin A2/MMP-13 loop, the activation of which contributes to joint destruction in RA, mainly through promoting invasion of FLS. Annexin A2 might therefore become a novel clinical target for RA treatment.

Zhao W ，Zhang C ，Shi M ，Zhang J ，Li M ，Xue X ，Zhang Z ，Shu Z ，Zhu J ，Mu N ，Li W ，Hao Q ，Wang Z ，Gong L ，Zhang W ，Zhang Y ... -  《-》

Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis.

Choi C ，Jeong W ，Ghang B ，Park Y ，Hyun C ，Cho M ，Kim J ... -  《-》

Cyr61 induces IL-6 production by fibroblast-like synoviocytes promoting Th17 differentiation in rheumatoid arthritis.

Lin J ，Zhou Z ，Huo R ，Xiao L ，Ouyang G ，Wang L ，Sun Y ，Shen B ，Li D ，Li N ... -  《-》