Epigenetic alterations in rheumatoid arthritis fibroblast-like synoviocytes

Abstract

Rheumatoid arthritis is an immune-mediated disease that primarily affects diarthrodial joints. Susceptibility and severity of this disease are influenced by nongenetic factors, such as environmental stress, suggesting an important role of epigenetic changes. In this review, we summarize the epigenetic changes (DNA methylation, histone modification and miRNA expression) in fibroblast-like synoviocytes, which are the joint-lining mesenchymal cells that play an important role in joint inflammation and damage. We also review the effects of these epigenetic changes on rheumatoid arthritis pathogenesis and discuss their therapeutic potential.

Keywords: epigenetics; fibroblast-like synoviocytes; histone; methylation; microRNA; rheumatoid arthritis.

Figure 1.. Unique DNA methylation signatures in rheumatoid arthritis fibroblast-like synoviocytes from early and long-standing disease.

Principal component analysis shows differentially methylated loci in ERA, LRA, JIA and OA FLS lines. Methylation patterns in RA FLS lines segregate from OA FLS lines, while ERA FLS lines further segregate from LRA FLS lines. ERA: Early rheumatoid arthritis; FLS: Fibroblast-like synoviocytes; JIA: Juvenile idiopathic arthritis; LRA: Longstanding rheumatoid arthritis; OA: Osteoarthritis; RA: Rheumatoid arthritis. Adapted with permission from [29].

Figure 2.. LBH regulates the fibroblast-like synoviocyte transcriptome.

Heatmap showing gene expression in control (C) FLS and FLS in which LBH has been KD or OE. Probes include genes with significant (p < 0.05) differential expression between any two of the three FLS populations (control, KD and OE). Systems biology showed that cell cycle genes were enriched in the FLS with modulated LBH expression. Z scores represent gene expression levels and were calculated for each gene. FLS: Fibroblast-like synoviocyte; KD: Knocked-down; OE: Overexpressed. Adapted with permission from [37].

Figure 3.. Effect of histone deacetylase in a mouse model of autoantibody-mediated arthritis.

Male DBA/1 mice were injected with 2 mg of an anti-type II collagen monoclonal antibody cocktail on Day 0, and boosted with lipopolysaccharide on Day 2 to induce autoantibody-mediated arthritis. Mice were treated with 2.5 mg/kg of the HDAC inhibitor FK228 (n = 10) or saline control (n = 9) on Day 4. Graphs show the clinical score of arthritis severity over the disease course. FK228 has an immediate and dramatic effect of reducing arthritis. *p < 0.01. HDAC: Histone deacetylase. Adapted with permission from [61].