CircSLC7A2 protects against osteoarthritis through inhibition of the miR-4498/TIMP3 axis.
CircSLC7A2 protects against osteoarthritis through inhibition of the miR-4498/TIMP3 axis.
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DOI：
10.1111/cpr.13047
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发表时间：
2021-06
影响因子：
8.5
通讯作者：
Hu Z
中科院分区：
文献类型：
--
作者：
Ni W;Jiang C;Wu Y;Zhang H;Wang L;Yik JHN;Haudenschild DR;Fan S;Shen S;Hu Z
环状RNA（circRNA）是与其他内源性RNA种类（如microRNA）竞争的非编码RNA，并且已经涉及许多疾病。在这项研究中，我们研究了一种新的circRNA（circSLC 7A 2）在骨关节炎（OA）中的作用。真实的实时定量聚合酶链反应（RT-qPCR）显示，circSLC 7A 2在OA组织中的相对表达显著低于匹配对照。采用Western blotting、RT-qPCR和免疫荧光实验来评估circSLC 7A 2、miR-4498和TIMP 3的作用。还在小鼠模型中证实了circSLC 7A 2的体内作用和机制。在OA模型中，circSLC 7A 2减少，并且circSLC 7A 2的环化受到FUS的调节。circSLC 7A 2的缺失减少了miR-4498的海绵，并进一步抑制了TIMP 3的表达，随后导致炎症反应。我们进一步确定miR-4498抑制剂逆转了circSLC 7A 2敲低诱导的OA表型。关节内注射circSLC 7A 2缓解了前交叉韧带横断（ACLT）小鼠模型中的体内OA进展。软骨细胞catalysts和analysts的circSLC 7A 2/miR-4498/TIMP 3轴在OA发展中起关键作用。我们的研究结果表明，circSLC 7A 2可以作为骨关节炎的新的治疗靶点。新型环状RNA circSLC 7A 2的表达对于维持ECM稳态和保护软骨免受OA进展是重要的。CircSLC 7A 2受FUS调控，通过miR-4498/TIMP 3轴发挥作用，有效且全面地减轻炎症，抑制分解代谢酶，引入合成代谢酶，防止细胞凋亡，从而维持软骨ECM，从而预防或延缓OA进展。
Circular RNAs (circRNAs) are noncoding RNAs that compete against other endogenous RNA species, such as microRNAs, and have been implicated in many diseases. In this study, we investigated the role of a new circRNA (circSLC7A2) in osteoarthritis (OA). The relative expression of circSLC7A2 was significantly lower in OA tissues than it was in matched controls, as shown by real‐time quantitative polymerase chain reaction (RT‐qPCR). Western blotting, RT‐qPCR and immunofluorescence experiments were employed to evaluate the roles of circSLC7A2, miR‐4498 and TIMP3. The in vivo role and mechanism of circSLC7A2 were also conformed in a mouse model. circSLC7A2 was decreased in OA model and the circularization of circSLC7A2 was regulated by FUS. Loss of circSLC7A2 reduced the sponge of miR‐4498 and further inhibited the expression of TIMP3, subsequently leading to an inflammatory response. We further determined that miR‐4498 inhibitor reversed circSLC7A2‐knockdown‐induced OA phenotypes. Intra‐articular injection of circSLC7A2 alleviated in vivo OA progression in a mouse model of anterior cruciate ligament transection (ACLT). The circSLC7A2/miR‐4498/TIMP3 axis of chondrocytes catabolism and anabolism plays a critical role in OA development. Our results suggest that circSLC7A2 may serve as a new therapeutic target for osteoarthritis. The expression of the novel circular RNA, circSLC7A2, is important for maintaining ECM homeostasis and protecting cartilage against OA progression. CircSLC7A2 is regulated by FUS and functions through miR‐4498/TIMP3 axis, which is effective and comprehensive in alleviating inflammation, inhibiting catabolic enzymes, introducing anabolic enzymes and preventing cell apoptosis that resulted in maintaining cartilage ECM, thus preventing or delaying OA progression.
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