Background/Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the joints. The inflammatory process causes the activation of synovial fibroblasts (SFs) and the destruction of articular cartilage and bone, resulting in disability of the joints. Both genetic and environmental factors have been shown to be associated with the pathogenesis of RA. However, these factors are unable to explain the pathogenesis of RA completely. Epigenetic factors such as histone lysine methylation are suggested to be associated with the pathogenesis of RA. Epigenetics refers to heritable phenotypic changes that influence gene expression independently of the DNA sequence. Aberrant gene expression of MLL1, which catalyzes methylation of histone H3 lysine 4 (H3K4), has been reported in RASFs. The aim of this study is to elucidate the involvement of MLL1 in the pathogenesis of RA.

Methods: SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 expression in the cultured SFs was evaluated after stimulation with tumor necrosis factor α (TNFα). We examined the changes in the expression of RA-associated genes, including matrix metalloproteinases (MMP-1, MMP-3, MMP-9, and MMP-13), cathepsins (CTSK and CTSL), cytokines (IL-6, IL-8, IL-15, and IL-23A), and chemokines (CCL2, CCL3, CCL5, CXCL1, CXCL5, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, and CX3CL1), as well as the trimethylation of H3K4 (H3K4me3) levels in the promoters upon siRNA-mediated depletion of MLL1 in RASFs. The changes in the gene expression were also investigated by the treatment with an MLL1 inhibitor MM-102. The H3K4me3 levels in the cytokine and chemokine promoters were also examined in RASFs and OASFs.

Results: The levels of MLL1 mRNA and protein were higher after TNFα stimulation in RASFs versus OASFs. The mRNA levels of IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly decreased in MLL1 siRNA-treated RASFs. Correspondingly, the H3K4me3 levels in the promoters were significantly repressed. MM-102 significantly decreased CCL5, CXCL9, CXCL10, and CXCL11 mRNA levels in RASFs. MM-102 also repressed the H3K4me3 levels in the promoters in RASFs. In addition, the H3K4me3 levels in the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 promoters were significantly higher in RASFs than OASFs.

Conclusion: Study findings suggest that MLL1 regulates expression of the cytokines and chemokines that are involved in the pathogenesis of RASFs. MLL1 may be a new target for RA therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/histone-lysine-methyltransferase-mll1-regulates-the-expression-of-cytokines-and-chemokines-in-rheumatoid-arthritis-synovial-fibroblasts/