MicroRNA-1 Modulates Chondrocyte Phenotype by Regulating FZD7 of Wnt/β-Catenin Signaling Pathway
MicroRNA-1 Modulates Chondrocyte Phenotype by Regulating FZD7 of Wnt/β-Catenin Signaling Pathway
复制标题
MicroRNA-1 通过调节 Wnt/β-连环蛋白信号通路的 FZD7 来调节软骨细胞表型。
DOI：
10.1177/1947603520973255
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发表时间：
2020-11-20
期刊：
影响因子：
2.8
通讯作者：
Li, Jiao Jiao
中科院分区：
文献类型：
--
作者：
Yang, Yang;Wang, Yawei;Li, Jiao Jiao
目标。骨关节炎(OA)是一种以明显疼痛为特征的不治之症。MicroRNAs构成表观遗传学机制，可能通过促进软骨细胞表型的改变而影响骨性关节炎的进展。本研究首次探讨了miRNA-1(miR-1)与骨性关节炎发病机制之间是否存在联系，并探讨了相关的分子机制。设计。研究比较了非骨性关节炎和骨性关节炎软骨细胞以及高表达和低表达miR-1的SW1353细胞中与骨关节炎相关的基因表达，包括基质金属蛋白酶-13、ADAMTS5和COL2A1。生物信息学和荧光素酶报告实验证实FZD7是否是miR-1的靶点。研究miR-1对FZD7表达和下游Wnt/β-catenin信号转导的影响。结果。非骨性关节炎和骨性关节炎软骨细胞在miR-1和骨性关节炎相关基因的表达上存在显著差异。在SW1353细胞中，MIR-1过表达和过低表达分别降低和增强了与软骨分解代谢相关的基因表达。FZD7在Wnt/β-catenin信号通路中具有重要作用，是miR-1的潜在靶点。MIR-1与FZD7结合增加了磷酸化(失活)的β-连环蛋白水平，从而阻止了下游的β-连环蛋白信号转导。结论。在软骨细胞中，miR-1抑制Wnt/β-catenin信号可能会减弱调节分解代谢酶活性的基因的表达。这一发现可能对将来研究治疗骨性关节炎的分子靶点有用。
Objective. Osteoarthritis (OA) is an incurable joint disease characterized by pronounced pain. MicroRNAs constitute epigenetic mechanisms that may affect OA progression by contributing to changes in chondrocyte phenotype. This study investigates for the first time whether there is a link between miRNA-1 (miR-1) and OA pathogenesis, and the molecular mechanisms involved. Design. OA-associated gene expression, including MMP-13, ADAMTS5, and COL2A1 was compared in chondrocytes from non-OA and OA cartilage, and in SW1353 cells over- and underexpressing miR-1. Bioinformatics and luciferase reporter assay were conducted to confirm whether FZD7 was a target of miR-1. The effects of miR-1 on FZD7 expression and downstream Wnt/beta-catenin signalling were investigated. Results. Non-OA and OA chondrocytes differed significantly in the expression of miR-1 and OA-associated genes. MiR-1 over- and underexpression in SW1353 cells, respectively, reduced and enhanced gene expression associated with cartilage catabolism. FZD7, which has an important role in the Wnt/beta-catenin signaling pathway, was shown to be a potential target of miR-1. MiR-1 binding to FZD7 increased the levels of phosphorylated (inactivated) beta-catenin, thereby preventing downstream beta-catenin signaling. Conclusions. Inhibition of Wnt/beta-catenin signaling by miR-1 in chondrocytes may attenuate the expression of genes that regulate the activity of catabolic enzymes. This finding may be useful for future investigations of molecular targets for OA treatment.