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

诱导类风湿性关节炎骨破坏的滑膜成纤维细胞亚群的鉴定

• 批准号: 19J21942
• 负责人: 顔 明露
• 金额: $ 1.98万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2019
• 资助国家: 日本
• 起止时间: 2019-04-25 至 2022-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-19J21942/
• 关键词: Rheumatoid arthritis; RANKL; tissue destruction; Bone destruction; Synovial fibroblasts; osteoclastogenesis

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.

类风湿性关节炎（RA）是最常见的以炎症和关节破坏为特征的自身免疫性疾病之一。RA患者的关节破坏通常是不可逆的，这往往导致关节功能的永久性丧失和随后的残疾。在这项研究中，我们的目的是研究关节炎关节损伤的分子机制。我们对关节炎发炎关节的滑膜细胞进行了scRNA-seq分析。滑膜细胞的无监督聚类揭示了几种细胞类型，其中成纤维细胞特异性地高度表达关节破坏性基因，如TNFSF 11和MMP（分别编码RANKL和MMP）。在研究成纤维细胞群体时，我们发现这些破坏性基因在一个成纤维细胞簇中特异性富集，我们随后将成纤维细胞群体命名为“组织破坏性成纤维细胞”。关节炎成纤维细胞的染色质分析进一步鉴定了位于RANKL和MMPs基因位点上游的远端调控元件。一种称为溴结构域蛋白4（BRD 4）的活性增强子的小分子抑制剂基本上抑制了RANKL和MMP的表达。因此，诱导RANKL和MMPs异常的表观遗传学机制可能是： 导致RA关节损伤。

项目成果

A distal enhancer regulates RANKL expression in synovial fibroblasts in arthritis

远端增强子调节关节炎滑膜成纤维细胞中的 RANKL 表达

• 发表时间: 2021
• 作者: Minglu Yan;Noriko Komatsu;Ryunosuke Muro;Takeshi Nitta;Kazuo Okamoto;Masayuki Tsukasaki;Hiroshi Takayanagi
• 通讯作者: Hiroshi Takayanagi

Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis

• DOI: 10.1172/jci143060
• 发表时间: 2021-03-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Komatsu, Noriko;Win, Stephanie;Takayanagi, Hiroshi
• 通讯作者: Takayanagi, Hiroshi