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SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

2017; Impact Journals LLC; Volume: 8; Issue: 51 Linguagem: Inglês

10.18632/oncotarget.21628

1949-2553

Jiangtao Guo, Wei Zhao, Xuqing Cao, Huiying Yang, Juan Ding, Jingbin Ding, Zifang Tan, Xiaoli Ma, Chunfang Hao, Lili Wu, Zhengjuan Ma, Jian‐Jun Xie, Zhijun Wang,

Toxin Mechanisms and Immunotoxins

// Jiangtao Guo 1, 2, * , Wei Zhao 1, * , Xuqing Cao 1, 2, * , Huiying Yang 1 , Juan Ding 1 , Jingbin Ding 1 , Zifang Tan 1, 2 , Xiaoli Ma 1, 2 , Chunfang Hao 1, 2 , Lili Wu 1, 2 , Zhengjuan Ma 3 , Jianjun Xie 4 and Zhijun Wang 1 1 Cancer Hospital of General Hospital, Affiliated Ningxia People's Hospital, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, China 2 Ningxia People's Hospital, Yinchuan, China 3 The Fifth People's Hospital of Ningxia, Shizuishan, China 4 Pingluo People's Hospital, Pingluo, China * These authors have contributed equally to this work Correspondence to: Zhijun Wang, email: wangzhijun1978@hotmail.com Keywords: rheumatoid arthritis, invasion, fibroblast-like synoviocytes, SIRT1, deacetylation Received: February 23, 2017 Accepted: August 26, 2017 Published: October 06, 2017 ABSTRACT Suppression of tissue inhibitor of matrix metalloproteinase (TIMP) is associated with the tumor-like invasion of fibroblast-like synoviocytes (FLSs) that occurs during rheumatoid arthritis-related cartilage destruction. Silent information regulator 2 homolog1 (SIRT1), a histone deacetylase, is widely involved in transcriptional regulation, genomic stability, metabolism and DNA repair. Recent studies suggest that SIRT1 may also impact inflammatory response and the proliferation of FLSs in rheumatoid arthritis (RA). However, it is unknown whether SIRT1 has a role in the tumor-like invasion of FLSs in rheumatoid arthritis. Herein we report that SIRT1 contributes to FLS invasion and cartilage destruction via a TIMP1-dependent mechanism. Elevated SIRT1 in RA synovia suppresses TIMP1 expression via deacetylation of TIMP1-associated histones, thereby disrupting the binding of the transcription factor specificity protein 1 (Sp1) to the TIMP1 promoter. In rats with collagen-induced arthritis, depletion of SIRT1 remarkably promoted TIMP1 expression in synovial tissues and ameliorated cartilage destruction. These results describe a new role for SIRT1 and demonstrate its potential value as a therapeutic target for rheumatoid arthritis.