MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis
MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis
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MicroRNA-218-5p作为治疗人类骨关节炎的潜在靶点
DOI：
10.1016/j.ymthe.2017.08.009
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发表时间：
2017-12-06
影响因子：
12.4
通讯作者：
Im, Hee-Jeong
中科院分区：
文献类型：
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作者：
Lu, Jun;Ji, Ming-liang;Im, Hee-Jeong
新的证据表明，失调的microRNAs(MiRNAs)在骨关节炎(OA)中起着关键作用，但特定的miRNAs的作用尚不清楚。因此，我们确定了与OA相关的miRNAs，并对结果进行了功能验证。在这里，我们证明miR-218-5p在中、重度骨性关节炎中显著上调，并与改良的Mankin评分相关。通过功能获得和功能丧失的研究表明，miR-218-5p显著影响基质合成基因的表达和软骨细胞的增殖和凋亡。利用SW1353和C28/I2细胞，PIK3C2AmRNA被鉴定为miR-218-5p的靶标。MiR-218-5p的下调显著促进了PIK3C2A及其下游靶蛋白Akt、mTOR、S6和4EBP1的表达。更重要的是，与对照组相比，暴露于miR-218-5p抑制剂的OA小鼠免受软骨退化的保护，并减少了蛋白多糖的损失和关节软骨细胞的损失。MIR-218-5P是一种通过调节PI3K/Akt/mTOR信号通路而导致软骨破坏的新的诱导剂。抑制内源性miR-218-5p的表达/活性似乎是治疗OA的一个有吸引力的方法。
Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.