Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheum
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RESEARCH ARTICLE
Open Access
Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis Changmin Choi1, Wooseong Jeong2, Byeongzu Ghang2, Yonggeun Park3, Changlim Hyun4, Moonjae Cho5* and Jinseok Kim2*
Abstract Background: Interleukin-6 (IL-6) is involved in fibroblast-like synoviocyte (FLS) activation and promotes pannus formation and bone and cartilage destruction in rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61) protein regulates cell proliferation, migration, and differentiation. The aim of this study was to investigate the role of Cyr61 in RA-FLS migration and invasion after IL-6 stimulation. Methods: Western blotting, immunohistochemistry, reverse transcription-polymerase chain reaction, and real timepolymerase chain reaction were used to examine protein and mRNA levels of Cyr61, matrix metalloproteinases (MMPs), and other signalling proteins. Knockdown of gene expression was performed with siRNA, and RNA sequencing was performed for differential gene analysis. Migration and invasion were assessed by wound healing and Boyden chamber assays. Results: Cyr61 levels were elevated in FLSs from RA patients compared to those in osteoarthritis patients. Control and IL-6-treated FLSs showed differential gene expression. IL-6 stimulated protein synthesis of Cyr61, which was attenuated by the extracellular signal-related kinase 1/2 (ERK 1/2) inhibitor, PD98059, and knockdown of early growth response 3 (EGR3), but not of JUN. IL-6induced Cyr61 protein synthesis increased expression of MMP2. Cyr61 promoted FLS migration and invasion in an autocrine manner. Knockdown of CYR61 and a neutralising antibody attenuated Cyr61 synthesis and IL-6-induced FLS migration. Conclusions: By modulating the ERK/EGR3 pathway, IL-6 stimulated Cyr61 production and in turn increased invasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA. Keywords: Cyr61, Interleukin-6, Extracellular signal-regulated kinase, Fibroblast-like synoviocyte, Rheumatoid arthritis
Background Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes destruction of cartilage and bone and systemic inflammation via the interactions of different types of inflammatory cells [1, 2]. Fibroblast* Correspondence: [email protected]; [email protected] 5 Department of Biochemistry, Jeju National University School of Medicine, Aran 13gil, Jeju 690-797, Republic of Korea 2 Department of Internal Medicine, Division of Rheumatology, Jeju National University Hospital, Aran 13gil, Jeju 690-797, Republic of Korea Full list of author information is available at the end of the article
like synoviocytes (FLSs) play an important role in the pathogenesis of RA and are major components of the hyperplastic pannus that invades cartilage and bone. These cells contribute to the local production of proinflammatory cytokines and enzymes that degrade the extracellular matrix (ECM) [3]. In addition, RA FLSs present a tumour-like
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