Inhibition of miR-490-5p Promotes Human Adipose-Derived Stem Cells Chondrogenesis and Protects Chondrocytes via the PITPNM1/PI3K/AKT Axis.
Inhibition of miR-490-5p Promotes Human Adipose-Derived Stem Cells Chondrogenesis and Protects Chondrocytes via the PITPNM1/PI3K/AKT Axis.
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抑制 miR-490-5p 可促进人脂肪干细胞软骨形成并通过 PITPNM1/PI3K/AKT 轴保护软骨细胞
DOI：
10.3389/fcell.2020.573221
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发表时间：
2020
影响因子：
5.5
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Li H;Zhao X;Wen X;Zeng A;Mao G;Lin R;Hu S;Liao W;Zhang Z
MicroRNAs （miRNAs）在骨关节炎（OA）的软骨发育和体内平衡中起着关键作用。虽然mirna在软骨退行性变中的基本作用已被广泛研究，但它们对人脂肪源性干细胞（hADSCs）诱导的软骨分化的影响及其潜在机制在很大程度上仍是未知的。在这里，我们研究了mirna在hADSC软骨分化和软骨细胞稳态中的作用和机制。通过微阵列分析，我们筛选了软骨分化hscs中表达的miRNA，并鉴定出miR-490-5p是下调最显著的miRNA。我们分析了其在体内和体外软骨形成过程中的表达模式。我们的研究表明，miR-490-5p过表达促进了hscs从软骨形成到成骨形成的转变。此外，基于miRNA-mRNA预测分析和双荧光素酶报告基因检测，我们提出并证明了miR-490-5p通过结合PITPNM1的3 ' -UTR并抑制其翻译来靶向PITPNM1。此外，功能缺失和功能获得实验确定了PI3K/AKT信号通路的参与，一项拯救实验确定了miR-490-5p/PITPNM1/PI3K/AKT轴在hADSC软骨分化和软骨细胞稳态中的作用和具体机制。通过内侧半月板（DMM） OA模型的失稳证实，抑制miR-490-5p可减轻体内软骨损伤。我们发现miR-490-5p是hadsc介导的软骨形成和软骨细胞表型的一种新型调节剂。本研究强调，miR-490-5p通过靶向PITPNM1激活PI3K/AKT信号通路，减弱hADSC软骨形成，加速软骨降解。抑制miR-490-5p促进hADSC软骨分化，并通过PITPNM1/PI3K/AKT轴保护软骨细胞表型，从而为OA治疗提供了新的干细胞潜在治疗靶点。
MicroRNAs (miRNAs) play a pivotal role in cartilage development and homeostasis in osteoarthritis (OA). While the fundamental roles of miRNAs in cartilage degeneration have been extensively studied, their effects on chondrogenic differentiation induced by human adipose-derived stem cells (hADSCs) and the underlying mechanisms remain largely elusive. Here, we investigated the roles and mechanisms of miRNAs in hADSC chondrogenic differentiation and chondrocyte homeostasis. Using microarray analysis, we screened miRNAs expressed in the chondrogenic differentiated hADSCs and identified miR-490-5p as the most significantly down-regulated miRNA. We analyzed its expression patterns during chondrogenesis in vivo and in vitro. Our study showed that miR-490-5p overexpression promoted the transition of hADSCs from chondrogenesis to osteogenesis. In addition, based on miRNA–mRNA prediction analysis and dual-luciferase reporter assay, we proposed and proved that miR-490-5p targeted PITPNM1 by binding to its 3′-UTR and inhibiting its translation. Moreover, loss- and gain-of-function experiments identified the involvement of the PI3K/AKT signaling pathway, and a rescue experiment determined the effect and specific mechanism of the miR-490-5p/PITPNM1/PI3K/AKT axis in hADSC chondrogenic differentiation and chondrocyte homeostasis. Inhibition of miR-490-5p alleviated cartilage injury in vivo as demonstrated using the destabilization of the medial meniscus (DMM) OA model. We identified miR-490-5p as a novel modulator of hADSC-mediated chondrogenesis and chondrocyte phenotype. This study highlighted that miR-490-5p attenuated hADSC chondrogenesis and accelerated cartilage degradation through activation of the PI3K/AKT signaling pathway by targeting PITPNM1. Inhibition of miR-490-5p facilitated hADSC chondrogenic differentiation and protected chondrocyte phenotype via the PITPNM1/PI3K/AKT axis, thus providing a novel stem cell potential therapeutic target for OA treatment.
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