MicroRNA-455-3p promotes TGF-β signaling and inhibits osteoarthritis development by directly targeting PAK2
MicroRNA-455-3p promotes TGF-β signaling and inhibits osteoarthritis development by directly targeting PAK2
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MicroRNA-455-3p 通过直接靶向 PAK2 促进 TGF-β 信号传导并抑制骨关节炎的发展
DOI：
10.1038/s12276-019-0322-3
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发表时间：
2019-10-04
影响因子：
12.8
通讯作者：
Zhang, Zhiqi
中科院分区：
文献类型：
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作者：
Hu, Shu;Zhao, Xiaoyi;Zhang, Zhiqi
MicroRNAs(miRNAs，miR)在骨关节炎的发病机制中起着关键作用。很少有研究研究P21激活的蛋白激酶(PAKs)在骨性关节炎中的调节作用，它是一个丝氨酸/苏氨酸激酶家族。本研究的目的是确定miR-455-3p是否可以通过靶向PAK2来调节骨性关节炎软骨退变。MIR-455-3p基因敲除小鼠膝关节软骨明显退变。在人脂肪干细胞(HADSC)软骨形成的晚期和OA影响的软骨细胞中，MIR-455-3p的表达增加，PAK2的表达降低。此外，在miR-455-3p过表达的软骨细胞和PAK2抑制的软骨细胞中，软骨特异基因上调，肥大相关基因下调。荧光素酶报告实验证实，miR-455-3p通过直接靶向PAK2 mRNA的3‘非翻译区(3’UTRs)来调节PAK2的表达。PAK抑制剂IPA-3可抑制骨性关节炎所致的软骨退变。此外，抑制PAK2可促进软骨细胞中转化生长因子/Smad信号通路中R-Smad的激活。综上所述，我们的结果提示miR-455-3p促进软骨细胞内的转化生长因子-β/Smad信号转导，并通过直接抑制PAK2来抑制软骨退变。这些结果表明miR-455-3P和PAK2分别是治疗骨性关节炎的新的潜在的治疗药物和靶点。
MicroRNAs (miRNAs, miR) play a key role in the pathogenesis of osteoarthritis (OA). Few studies have examined the regulatory role of P21-activated kinases (PAKs), a family of serine/threonine kinases, in OA. The aim of this study was to determine whether miR-455-3p can regulate cartilage degeneration in OA by targeting PAK2. MiR-455-3p knockout mice showed significant degeneration of the knee cartilage. MiR-455-3p expression increased and PAK2 expression decreased in the late stage of human adipose-derived stem cell (hADSC) chondrogenesis and in chondrocytes affected by OA. Furthermore, in both miR-455-3p-overexpressing chondrocytes and PAK2-suppressing chondrocytes, cartilage-specific genes were upregulated, and hypertrophy-related genes were downregulated. A luciferase reporter assay confirmed that miR-455-3p regulates PAK2 expression by directly targeting the 3'-untranslated regions (3'UTRs) of PAK2 mRNA. IPA-3, a PAK inhibitor, inhibited cartilage degeneration due to OA. Moreover, suppressing PAK2 promoted R-Smad activation in the TGF/Smad signaling pathway in chondrocytes. Altogether, our results suggest that miR-455-3p promotes TGF-beta/Smad signaling in chondrocytes and inhibits cartilage degeneration by directly suppressing PAK2. These results thus indicate that miR-455-3p and PAK2 are novel potential therapeutic agents and targets, respectively, for the treatment of OA.