MicroRNA-320c inhibits development of osteoarthritis through downregulation of canonical Wnt signaling pathway
MicroRNA-320c inhibits development of osteoarthritis through downregulation of canonical Wnt signaling pathway
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MicroRNA-320c 通过下调经典 Wnt 信号通路抑制骨关节炎的发展
DOI：
10.1016/j.lfs.2019.05.011
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发表时间：
2019-07-01
期刊：
影响因子：
6.1
通讯作者：
Zhang, Zhiqi
中科院分区：
文献类型：
--
作者：
Hu, Shu;Mao, Guping;Zhang, Zhiqi
目的：骨关节炎（OA）是导致老年人畸形的主要原因。新的证据表明microRNA和Wnt信号通路与其发病机制有关。我们的目的是确定是否microRNA-320 c抑制骨关节炎的发展，通过抑制Wnt信号pathway.Materials and Methods：MiR-320 c和β-连环蛋白的表达进行了评估，在人脂肪来源的干细胞（hADSC）模型的软骨形成和正常和OA的原代人软骨细胞。分别用miR-320 c或其反义抑制剂和β-catenin siRNA转染OA软骨细胞。通过荧光素酶报告基因检测证实miR-320 c与β-catenin mRNA之间的直接相互作用以及β-catenin/TCF复合物的活性。在胶原酶诱导的OA小鼠模型中关节内注射Mmu-miR-320- 3 p阿戈米尔。主要发现：OA软骨细胞和hADSC软骨形成晚期MiR-320 c表达减少，β-catenin表达增加。过表达miR-320 c和敲低β-catenin具有相似的效果，即软骨特异性基因在OA软骨细胞中升高，肥大相关基因在OA软骨细胞中下调。荧光素酶报告基因检测证实miR-320 c通过直接靶向β-catenin mRNA的3 'UTR调控β-catenin的表达，并降低β-catenin/TCF复合物的相对转录活性。注射mmu-miR-320- 3 p可减弱OA小鼠模型中的OA进展。意义：我们的结果支持miR-320 c可通过抑制经典Wnt信号通路来抑制骨关节炎软骨细胞的变性，并表明miR-320 c作为骨关节炎治疗的新型治疗剂的潜力。
Aims: Osteoarthritis (OA) is a leading cause of deformity in aging people. Emerging evidence suggests that microRNAs and Wnt signaling pathway are associated with its pathogenesis. We aimed to determine whether microRNA-320c inhibits the development of osteoarthritis by suppressing Wnt signaling pathway.Materials and methods: MiR-320c and beta-catenin expression was assessed in human adipose derived stem cells (hADSCs) model of chondrogenesis and in normal and OA primary human chondrocytes. OA chondrocytes were transfected with miR-320c or its antisense inhibitor and beta-catenin siRNA respectively. Direct interaction between miR-320c and beta-catenin mRNA as well as activity of beta-catenin/TCF complex were confirmed by luciferase reporter assay. Mmu-miR-320-3p agomir was intra-articularly injected in collagenase-induced OA mouse model. OA progression was evaluated histologically and immunohistochemically.Key findings: MiR-320c was decreased and beta-catenin was increased in OA chondrocytes and late stage of hADSCs chondrogenesis. Overexpression of miR-320c and knockdown of beta-catenin had similar effects that the cartilage-specific genes were elevated and hypertrophy-related genes were down-regulated in OA chondrocytes. Luciferase reporter assay confirm that miR-320c regulated the expression of beta-catenin by directly targeting 3'UTR of beta-catenin mRNA and decreased the relative transcriptional activity of the beta-catenin/TCF complex. Injection of mmu-miR-320-3p attenuated OA progression in the OA mouse model.Significance: Our results supports that miR-320c can inhibits the degeneration of osteoarthritis chondrocytes via suppressing the canonical Wnt signaling pathway and indicates the potential of miR-320c as a novel therapeutic agent for osteoarthritis treatment.