2021 Fiscal Year Annual Research Report
関節リウマチの骨破壊を誘導する滑膜線維芽細胞サブセットの同定
| Project/Area Number |
19J21942
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| Research Institution | The University of Tokyo |
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Principal Investigator |
顔 明露 東京大学, 大学院医学系研究科, 特別研究員(DC1)
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| Project Period (FY) |
2019-04-25 – 2022-03-31
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| Keywords | Rheumatoid arthritis / RANKL / tissue destruction |
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| Outline of Annual Research Achievements |
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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| Research Progress Status |
令和3年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
令和3年度が最終年度であるため、記入しない。
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[Journal Article] Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.2021
Author(s)
Noriko Komatsu, Stephanie Win, Minglu Yan, Nam Cong-Nhat Huynh, Shinichiro Sawa, Masayuki Tsukasaki, Asuka Terashima, Warunee Pluemsakunthai, George Kollias, Tomoki Nakashima, Hiroshi Takayanagi
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Journal Title
J Clin Invest.
Volume: 131(6)
Pages: e143060
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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