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MicroRNA-9 ameliorates destructive arthritis through down-regulation of NF-κB1-RANKL pathway in fibroblast-like synoviocytes.
Clinical Immunology ( IF 8.6 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.clim.2020.108348
Wen Shi Lee 1 , Shinsuke Yasuda 2 , Michihiro Kono 1 , Yuki Kudo 1 , Sanae Shimamura 1 , Michihito Kono 1 , Yuichiro Fujieda 1 , Masaru Kato 1 , Kenji Oku 1 , Tomohiro Shimizu 3 , Tomohiro Onodera 3 , Norimasa Iwasaki 3 , Tatsuya Atsumi 1
Affiliation  

We investigated the effect of miR-9 on fibroblast-like synoviocytes (FLS) from RA patients and animal arthritis model. The binding of miR-9 to NF-κB1 3'UTR was analyzed by luciferase reporter assay and immunoprecipitation. ChIP assay and luciferase promoter assay were performed to identify the binding of NF-κB1 to RANKL promoter and its activity. FLS were treated with miR-9/anti-miR-9 to evaluate cell proliferation and the expression of RANKL. Therapeutic effect of intra-articular miR-9 was evaluated in type-II collagen-induced arthritis in rats. miR-9 bound to the 3'-UTR of NF-κB1 and downregulated NF-κB1. NF-κB1 bound to RANKL promoter and increased the promoter activity of RANKL. RANKL was downregulated by miR-9. Proliferation of FLS was increased by miR-9 inhibitor. miR-9 dampened experimental arthritis by lowering inflammatory state, reducing RANKL and osteoclasts formation. Our findings revealed miR-9-NF-κB1-RANKL pathway in RA-FLS, further, miR-9 ameliorated inflammatory arthritis in vivo which propose therapeutic implications of miR- 9 in RA.

中文翻译:

MicroRNA-9通过下调成纤维细胞样滑膜细胞中NF-κB1-RANKL途径来改善破坏性关节炎。

我们调查了miR-9对来自RA患者和动物关节炎模型的成纤维样滑膜细胞(FLS)的影响。miR-9与NF-κB13'UTR的结合通过荧光素酶报告基因分析和免疫沉淀法进行分析。进行ChIP测定和荧光素酶启动子测定以鉴定NF-κB1与RANKL启动子的结合及其活性。用miR-9 / anti-miR-9处理FLS,以评估细胞增殖和RANKL的表达。在II型胶原诱导的大鼠关节炎中评估了关节腔内miR-9的治疗效果。miR-9与NF-κB1的3'-UTR结合并下调NF-κB1。NF-κB1与RANKL启动子结合并增加RANKL的启动子活性。RANKL被miR-9下调。miR-9抑制剂可增加FLS的增殖。miR-9通过降低炎症状态来缓解实验性关节炎,减少RANKL和破骨细胞的形成。我们的发现揭示了RA-FLS中的miR-9-NF-κB1-RANKL途径,此外,miR-9改善了体内的炎症性关节炎,提示miR-9在RA中具有治疗意义。
更新日期:2020-01-22
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