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

Zhao, Wei; Zhang, Cun; Shi, Man; Zhang, Jian; Li, Meng; Xue, Xiaochang; Zhang, Zhao; Shu, Zhen; Jun, Zhu; Ma, Nan; Li, Weina; Hao, Qiang; Wang, Zhijun; Gong, Li; Zhang, Wei; Zhang, Yingqi

doi:10.1002/art.38696

Cited by 26 publications

(45 citation statements)

References 43 publications

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“…We uncovered the Collagen II–DDR2–activator protein 1 (AP‐1)–CYR61–ETS1–MMP1 loop in RA FLS. Considering our previously findings that DDR2 activated by Collagen II promotes MMP13 through regulating Runx‐2, AP‐1, or annexin A2, this study shed new lights on the mechanism of DDR2 in RA and all our data collectively showed that DDR2 regulates MMPs production via several reciprocal and overlapped signaling pathways and blockade of DDR2 activation may be a new economical and effective strategy for RA treatment.…”

Section: Introductionsupporting

confidence: 60%

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

Huang

et al. 2016

Journal of Bone and Mineral Research

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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.

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Section: Introductionsupporting

confidence: 60%

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

Huang

et al. 2016

Journal of Bone and Mineral Research

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“…synoviocytes from patients with rheumatoid arthritis are particularly able to invade and destroy joints (28)(29)(30). Careful histological observations of the architecture of fibrosis also suggest an important contribution of fibroblast invasion to IPF pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.Keywords: idiopathic pulmonary fibrosis; pathogenesis; fibroblast; invasion; migration Idiopathic pulmonary fibrosis (IPF) is a disease of great unmet medical need. Aberrant or overexuberant wound healing responses to chronic lung injury are now thought to be responsible for the excessive fibroblast accumulation and extracellular matrix deposition that distort the lung's architecture and compromise its function in IPF (1, 2). Better characterization of these abnormal responses to lung injury should provide a rich set of therapeutic targets for novel IPF therapies.The abnormal accumulation of fibroblasts is a central hallmark of fibrotic tissues, including the lung in IPF. In addition to fibroblast proliferation, fibroblast accumulation in pulmonary fibrosis appears to fundamentally depend on: (1) the migration of these cells to sites of tissue injury; and (2) their ability to invade extracellular matrix. Although migration

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“…In murine collagen-induced arthritis, annexin A2 promoted migration and invasion of fibroblast synoviocytes into cartilage, leading to cartilage destruction. Conversely, down-regulation of annexin A2 expression alleviated joint damage [29]. Moreover, annexin A2 levels in synovial tissue were higher in RA patients than in OA patients [29].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, down-regulation of annexin A2 expression alleviated joint damage [29]. Moreover, annexin A2 levels in synovial tissue were higher in RA patients than in OA patients [29]. …”

Section: Discussionmentioning

confidence: 99%

Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis

Pianta¹,

Drouin²,

Crowley³

et al. 2015

Clinical Immunology

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In this study, autoantibody responses to annexin A2 were found in 11–15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.

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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

Cited by 26 publications

References 43 publications

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

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

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis

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