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Original Article

Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 expression by fibroblast-like synoviocytes

Tianhang ZhaiDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Chenxin GaoDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China,

Rongfen HuoDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Huiming ShengDepartment of Laboratory Medicine, Affiliated Tongren Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Songtao SunDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China,

Jun XieDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China,

Yong HeDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China,

Huali GaoDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China,

Huidan LiDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Jie ZhangDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Haichuan LiDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Yue SunDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China, ;Department of Rheumatoloy, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China, and

Jinpiao LinDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China, ;Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China

Baihua ShenDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China,

Lianbo XiaoDepartment of Bone Surgery, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China, Correspondence[email protected]

Ningli LiDepartment of Autoimmune Disease, Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China, Correspondence[email protected]

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Abstract

Objectives: The aim of this study was to investigate the effect and potential mechanism of Cysteine-rich 61 (Cyr61) on stimulating MMP-3 expression by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients.

Methods: Primarily cultured RA FLS were treated with exogenous Cyr61 protein or Cyr61-siRNA, then, MMP-3 expression was analyzed by real-time PCR, western blotting and ELISA. Signal transduction pathways in Cyr61-induced MMP-3 production were examined by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as control and MMP-3 in the joint was detected by IHC, real-time PCR and western blotting.

Results: High expressed MMP-3 and Cyr61 were positively correlated in RA ST; Cyr61 stimulated MMP-3 production in FLS of RA patients in an IL-1β and TNF-α independent manner. Cyr61 induced MMP-3 could further enhance the invasive ability of RA FLS. Mechanistically, we found that Cyr61 promoted MMP-3 production via the P38, JNK-dependent AP-1 signaling pathway. Blockage of Cyr61 function with monoclonal antibody could decrease MMP-3 expression in the joints of CIA mice.

Conclusion: This study provides new evidence that Cyr61 participates in RA pathogenesis not only as a pro-inflammatory factor but also plays a key role in bone erosion via promoting MMP-3 expression. We suggest that targeting of Cyr61 may represent a potential strategy in RA treatment.

Keywords:

Acknowledgements

This work was supported by Science and Technology Commission of Shanghai Municipality (12JC1407700, 12401903700, 12401903702, 15ZR1437900), Third Shanghai Fund for Traditional Chinese Medicine clinical advantages orthopedic specialist (ZYSNXD-YL-YSZK016).

Conflict of interest

None.

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Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 expression by fibroblast-like synoviocytes

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Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 expression by fibroblast-like synoviocytes

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