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

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.

Intervening up-regulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes.

“…Previously, it was reported that IL-10 works as an anti-in ammatory cytokine, inhibits VEGF [41], and suppresses in ammatory response [42]. The increased Timp1 has been reported to ameliorate cartilage destruction in collagen-induced arthritis in rats [43]. All these ndings are in accordance with our hypothesis that the amino acid transporter SLC7A5 takes part in cellular invasion and regulates protein levels of MMP3 and MMP13 via mTOR signaling pathway in RA FLS.…”

Intervening the up-regulated SLC7A5 could mitigate the inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes.

“…Previous literature reported that these cytokines, like IL-10 works as an anti-inflammatory cytokine, inhibits VEGF [37], decrease the inflammatory responses [38]. The increased Timp1 could ameliorate cartilage destruction in collagen-induced arthritis in rats [39]. All these findings are accord with our hypothesis that the amino acid transport SLC7A5 took part in invasion via regulating the protein expression of MMP3 and MMP13 in RA FLS.…”

Transformation of fibroblast‐like synoviocytes in rheumatoid arthritis; from a friend to foe

“…Synovial hyperplasia is frequently seen in RA synovium, which results from the accumulation of FLSs and MLSs in a specific inflammatory microenvironment [ 12 – 14 ]. RA FLSs display cancerous properties in inflamed synovial tissue, whereby they exhibit local tumor-like destructive and invasive characteristics [ 15 , 16 ]. The phenotype, behavior, and role of FLSs in RA resemble the fundamental role of cancer-associated fibroblasts (CAFs) in various cancers [ 17 , 18 ].…”