Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium, which eventually leads to the destruction of the joints. Epigenetic alteration (the mechanism of regulation of gene expression without changes in the DNA sequence), such as low levels of DNA methylation, is one of the factors that worsens the state of RA. However, the mechanism by which the alterations occur remains largely unknown.
In the present study, we identified a UHRF1 epigenetic regulator that was remarkably regulated in synovial fibroblasts (SF) of arthritis model mice and RA patients. A previous study showed that UHRF1 is a key player in maintaining DNA methylation, although the function of RA is unknown. To understand UHRF1 function for arthritis, we generated mice with SF-specific UHRF1 conditional knockout (cKO) and experimental arthritis was induced.
CKO mice exhibited more severe arthritic phenotypes than litter control. Next, to reveal UHRF1 function in SF, RNA-seq and MBD-seq were performed using SF obtained from control and cKO mice. Integrating genome-wide analyzes of the transcriptome and methyloma showed that the expression of several cytokines was upregulated in UHRF1-deficient SF accompanied by reduced DNA methylation signatures.
In addition, UHRF1 expression in the synovium was negatively correlated with various pathogenesis in RA patients. These data suggest that the pathogenesis of RA is exacerbated when UHRF1 levels are low in SF. Finally, we evaluated whether UHRF1 stabilization contributes to the improvement of arthritis pathogenesis. Ryuvidine, which was identified as a candidate chemical candidate for the UHRF1 stabilized protein, was administered to arthritis model mice.
The results showed that the pathogenesis of arthritis was improved with treatment with Ryuvidine. In addition, the development of RA-SF-derived organoids was suppressed by Ryuvidine.
This study demonstrated that UHRF1 expressed in SF with RA has a protective role in the suppression of multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be a therapeutic strategy for RA.