CircCDK14 protects against Osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2
CircCDK14 protects against Osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2
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CircCDK14 通过海绵 miR-125a-5p 并促进 Smad2 的表达来预防骨关节炎
DOI：
10.7150/thno.45993
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Xing
中科院分区：
文献类型：
--
作者：
Shen, Panyang;Yang, Yute;Zhao, Xing
理由：骨关节炎（OA）是全球最常见的关节疾病。以往的研究认为，软骨组织中细胞外基质（ECM）的分解和粘附之间的失衡是其主要原因。迄今为止，尽管有一些对症治疗，但OA仍无法治愈。本研究旨在探讨新型circRNA因子CircCDK 14在OA发生发展中的作用，并阐明其分子机制。研究方法：采用免疫印迹（WB）、免疫荧光（IF）、RNA免疫沉淀（RIP）、定量RT-PCR、荧光素酶分析和荧光原位杂交（FISH）等方法，研究CircCDK 14在OA中的作用及其与下游靶点（miR-125 a-5 p）和mRNA靶点（Smad 2）的相互作用。采用兔模型研究CircCDK 14在OA中的作用及机制。结果如下：在我们目前的研究中，我们发现CircCDK 14在关节佩戴位置下调的同时，调节软骨中的代谢，抑制凋亡并促进增殖。CircCDK 14的保护作用机制可能是通过miR-125 a-5 p的海绵化作用，下调Smad 2的表达，导致TGF-β信号通路功能障碍。关节内注射腺相关病毒-CircCDK 14也减轻了兔模型中的OA。结论：我们的研究揭示了CircCDK 14/miR-125 a-5 p/Smad 2轴在OA进展中的重要作用，并为OA的治疗提供了潜在的分子治疗策略。
Rationale: Osteoarthritis (OA) is the most common joint disease worldwide. Previous studies have identified the imbalance between extracellular matrix (ECM) catabolism and anabolism in cartilage tissue as the main cause. To date, there is no cure for OA despite a few symptomatic treatments. This study aimed to investigate the role of CircCDK14, a novel circRNA factor, in the progression of OA, and to elucidate its underlying molecular mechanisms. Methods: The function of CircCDK14 in OA, as well as the interaction between CircCDK14 and its downstream target (miR-125a-5p) and mRNA target (Smad2), was evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation (RIP), quantitative RT-PCR, luciferase assay and fluorescence in situ hybridization (FISH). Rabbit models were introduced to examine the function and mechanism of CircCDK14 in OA in vivo. Results: In our present study, we found that CircCDK14, while being down-regulated in the joint wearing position, regulated metabolism, inhibited apoptosis and promoted proliferation in the cartilage. Mechanically, the protective effect of CircCDK14 was mediated by miR-125a-5p sponging, which downregulated the Smad2 expression and led to the dysfunction of TGF-β signaling pathway. Intra-articular injection of adeno-associated virus-CircCDK14 also alleviated OA in the rabbit model. Conclusion: Our study revealed an important role of CircCDK14/miR-125a-5p/Smad2 axis in OA progression and provided a potential molecular therapeutic strategy for the treatment of OA.