title: 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.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Tong-Lie
authors.initials: TL
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Jin-Tao
authors.initials: JT
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jin-Kang
authors.initials: JK
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Wang-Qian
authors.initials: WQ
authors.lastname: Zhang
authors.affiliation: Experiment Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Liu
authors.affiliation: Institute of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiao-Chang
authors.initials: XC
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Ying-Qi
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000473:pathology*; D001862:Bone Resorption / Q000473:pathology*; D002465:Cell Movement; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D000070820:Discoidin Domain Receptor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D017208:Rats, Wistar; D015398:Signal Transduction; D013583:Synovial Membrane / Q000473:pathology; D000070918:Synoviocytes / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D018836:Inflammation Mediators; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D018808:Transcription Factor AP-1; C000603239:DDR2 protein, human; D000070820:Discoidin Domain Receptor 2; D020781:Matrix Metalloproteinase 1
keywords: CYR61; DISCOIDIN DOMAIN RECEPTOR 2; FIBROBLAST-LIKE SYNOVIOCYTE; INVASION; RHEUMATOID ARTHRITIS