MicroRNA-21-5p as a novel therapeutic target for osteoarthritis

作者：Xiaobo Wang, Fengchao Zhao, Linhong Yi, Jinlong Tang, Zhengya Zhu, Yong Pang, Ye-Shuai Chen, Dongya Li, Kaijin Guo, Xin Zheng · 发表于：Lara D. Veeken · 年份：2019 · DOI：10.1093/rheumatology/kez102 · 被引用次数：61 · 研究领域：Osteoarthritis Treatment and Mechanisms、Total Knee Arthroplasty Outcomes、Knee injuries and reconstruction techniques

OBJECTIVE: Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. METHODS: The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. RESULTS: We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. F...