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A Novel p53/microRNA‐22/Cyr61 Axis in Synovial Cells Regulates Inflammation in Rheumatoid Arthritis
Author(s) -
Lin Jinpiao,
Huo Rongfen,
Xiao Lianbo,
Zhu Xianjin,
Xie Jun,
Sun Songtao,
He Yong,
Zhang Jie,
Sun Yue,
Zhou Zhou,
Wu Pinru,
Shen Baihua,
Li Dangsheng,
Li Ningli
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38142
Subject(s) - microrna , cyr61 , cancer research , inflammation , arthritis , synovial membrane , rheumatoid arthritis , biology , microbiology and biotechnology , gene , immunology , receptor , ctgf , growth factor , genetics
Objective We previously showed that Cyr61 acts to promote fibroblast‐like synoviocyte (FLS) proliferation and Th17 cell differentiation, suggesting that Cyr61 plays an important role in mediating the joint inflammation and damage in rheumatoid arthritis (RA). The aim of this study was to investigate whether Cyr61 expression is regulated at the posttranscription level, and if so, how this regulation connects to other etiologic factors in RA. Methods Expression of microRNA‐22 (miR‐22) in synovial tissue was detected by real‐time polymerase chain reaction (PCR) using miRNA‐specific TaqMan MGB probes. MicroRNA‐22 promoter activity was analyzed using a Dual‐Luciferase Reporter Assay. Cytokine expression was measured by enzyme‐linked immunosorbent assay, and the expression of other factors was measured by real‐time PCR or Western blotting. Results MicroRNA‐22 directly targeted the 3′‐untranslated region of Cyr61 messenger RNA and inhibited Cyr61 expression. Expression of miR‐22 was down‐regulated and was negatively correlated with Cyr61 expression in RA synovial tissue. Furthermore, wild‐type p53 activated miR‐22 transcription by binding to the promoter region of the miR‐22 gene, while the mutant forms of p53 frequently found in RA synovial tissue were shown to have lost the ability to activate miR‐22 expression. As a result, miR‐22 was down‐regulated, contributing to the overexpression of Cyr61 in RA FLS. Conclusion Our results not only reveal a novel mechanism whereby p53 is involved in the posttranscriptional regulation of Cyr61 expression via miRNA‐22, but also provide a molecular explanation for the role of somatic mutations of p53, which are frequently observed in RA synovial tissue, in the etiology of this autoimmune disease.