DNA Methylation as a Future Therapeutic and Diagnostic Target in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients' functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable "liquid biopsy", thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.

Keywords: DNA methylation; autoimmunity; biomarkers; epigenetics; rheumatoid arthritis; therapy.

Figure 1

The mechanism of DNA methylation. DNA methylation is exerted by DNA methyltransferases (DNMTs). DNMTs at the 5′-position of cytosine residues in CpG dinucleotides transfers methyl groups from SAM (S-adenosylmethionine) to SAH (S-adenosylhomocysteine); thus, 5-methylcytosine is formed.

Figure 2

Potential mechanism of differentially methylated genes in rheumatoid arthritis (RA) regulated by various epigenetic drugs. DNA methylation is exerted by DNMTs. DNMTs are influenced by various epigenetic drugs either inhibiting or activating DNMTs, which consequently results in modulation of gene expression. Down arrow indicates hypomethylated genes (STA3, IL-6, CXCL12, DUSP22, STAT4, IRF5, IFIH1), and up arrow indicates hypermethylated genes (DR3, IL-10, DUSP22) in RA.