Extracellular vesicles (Evs) participate in the development of rheumatoid arthritis (RA), but the mechanisms remain unclear. This study aimed to determine the mechanism by which microRNA‐34a (miR‐34a) contained in bone marrow mesenchymal stem cell (BM‐MSC)‐derived Evs functions in RA fibroblast‐like synoviocytes (RA‐FLSs). BM‐MSC‐derived Evs and an Evs inhibitor were extracted. A rat model of RA was established. miR‐34a gain‐ and loss‐of‐function experiments were performed, and the inflammation in rat synovial fluid and tissues was detected. The role of miR‐34a in RA‐FLSs was also measured in vitro. The target gene of miR‐34a was predicted using the online software TargetScan and identified using a dual‐luciferase reporter gene assay, and the activation of the ATM/ATR/p53 signalling pathway was assessed. BM‐MSC‐derived Evs mainly elevated miR‐34a expression, which reduced RA inflammation in vivo and inhibited RA‐FLS proliferation and resistance to apoptosis in vitro, while inhibited miR‐34a expression enhanced RA development. In addition, miR‐34a could target cyclin I to activate the ATM/ATR/p53 signalling pathway, thus inhibiting abnormal RA‐FLS growth and RA inflammation. Our study showed that miR‐34a contained in BM‐MSC‐derived Evs could reduce RA inflammation by inhibiting the cyclin I/ATM/ATR/p53 signalling pathway.

中文翻译：

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来自骨髓间充质干细胞的细胞外囊泡中的 miR-34a 通过细胞周期蛋白 I/ATM/ATR/p53 轴减少类风湿性关节炎炎症

细胞外囊泡 (Evs) 参与了类风湿性关节炎 (RA) 的发展，但其机制尚不清楚。本研究旨在确定骨髓间充质干细胞 (BM-MSC) 衍生的 Evs 中所含的 microRNA-34a (miR-34a) 在 RA 成纤维样滑膜细胞 (RA-FLS) 中发挥作用的机制。提取了 BM-MSC 衍生的 Evs 和 Evs 抑制剂。建立RA大鼠模型。进行了 miR-34a 功能获得和功能丧失实验，并检测了大鼠滑液和组织中的炎症。还在体外测量了 miR-34a 在 RA-FLS 中的作用。使用在线软件 TargetScan 预测 miR-34a 的靶基因，并使用双荧光素酶报告基因检测进行鉴定，并评估 ATM/ATR/p53 信号通路的激活。BM-MSC 衍生的 Evs 主要上调 miR-34a 表达，在体内减少 RA 炎症并在体外抑制 RA-FLS 增殖和抗凋亡，同时抑制 miR-34a 表达增强 RA 发展。此外，miR-34a 可以靶向细胞周期蛋白 I 激活 ATM/ATR/p53 信号通路，从而抑制 RA-FLS 异常生长和 RA 炎症。我们的研究表明，BM-MSC 衍生的 Evs 中含有的 miR-34a 可以通过抑制细胞周期蛋白 I/ATM/ATR/p53 信号通路来减轻 RA 炎症。