| 研究実績の概要 |
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases characterized by inflammation and joint destruction. Joint destruction in RA patients is usually irreversible, which often leads to the permanent loss of joint function and subsequent disability. In this study we aimed to investigate the molecular mechanisms underlying the arthritic joint damage. We performed scRNA-seq analysis of synovial cells of the inflamed joints of arthritis. Unsupervised clustering of synovial cells revealed several cell types, of which the fibroblasts specifically highly express the joint destructive genes such as TNFSF11 and MMPs (encoding RANKL and MMPs, respectively). Focusing on the fibroblast population, we found these destructive genes are specifically enriched in one fibroblast cluster, we subsequently named the fibroblast population as "tissue-destructive fibroblast". Chromatin analysis of the arthritic fibroblasts further identified the distal regulatory elements located upstream of the RANKL and MMPs gene loci. A small molecule inhibitor of active enhancers called bromodomain protein 4 (BRD4) substantially inhibited the expression of RANKL and MMPs. Thus, the epigenetic mechanisms inducing the abnormal RANKL and MMPs contribute to RA joint damage.
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