Synovial fibroblasts contribute to the genetic risk of rheumatoid arthritis through the synergistic action of cytokines

In rheumatoid arthritis (RA), synovial fibroblasts (SFs) produce pathogenic molecules in the inflamed synovium. Despite their potential importance, comprehensive understanding of SFs under inflammatory conditions remains elusive. Here, to elucidate the actions of SFs and their contributions to RA pathogenesis, we stimulated SFs with 8 proinflammatory cytokines and analyzed the outcome using genomic, epigenomic and transcriptomic approaches. We observed stimulated transcription of pathogenic molecules by SFs exposed to synergistically acting cytokines. Some RA risk loci were associated with the expression of certain specific genes. We also observed epigenomic remodeling in activated SFs. Moreover, RA risk loci were enriched in clusters of enhancers (super-enhancers) exposed to synergistic proinflammatory cytokines. Our results shed light on the importance of activated SFs in RA pathogenesis. They also suggest possible treatment strategies targeting epigenomic alterations in SFs by inhibition of candidate modulators including MTF1 and RUNX1.