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

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 time-polymerase 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-6-induced 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.

The Impact of Curcumin on the Inflammatory Profile of SW982 Cells in a Rheumatoid Arthritis Model

“…In our work the levels of MMP1 mRNA in groups incubated with IL-6 and with IL-6 in presence curcumin were substantially lower than in the control. These outcomes seem to corroborate the results obtained by Choi et al [ 27 ], proving that IL-6 does not increase MMP-1 production in synoviocytes.…”

Identification and Validation of ATF3 Serving as a Potential Biomarker and Correlating With Pharmacotherapy Response and Immune Infiltration Characteristics in Rheumatoid Arthritis

“…Liu once reported that Sonic Hedgehog (SHH) signaling pathway mediates migration of RA-FLSs via MAPK/ERK pathway and may contribute to the progression of RA ( Liu et al, 2018 ). Choi also revealed that IL-6-regulated Cyr61 is a key player in FLS migration and invasion and eventually contributes to joint destruction in RA ( Choi et al, 2020 ). Similarly, our results also validated that ATF3 overexpression could promote the migration of RA-FLSs, while knockdown of ATF3 reduced the migration ability of FLSs.…”

CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

“…CCN1 and CCN2 have similar roles in RA pathogenesis, as both favour fibroblast-like synoviocite proliferation and induce osteoclastogenesis as well as angiogenesis (Chen et al 2017a , 2017b ; Ding et al 2016 ; Ganesan and Rasool 2017 ; Nozawa et al 2009 ; Zhang et al 2009 ). Moreover, CCN1 induces the expression of the proinflammatory cytokine IL-6 (Choi et al 2020 ; Lin et al 2012 ), IL8 and CCL20 which promote neutrophil and monocyte migration to the synovium (Chen et al 2017a ; Zhu et al 2015 ), and MMPs, which foster cell migration (Kwon et al 2017 ).…”