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.