miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage
miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage
复制标题
miR-105/Runx2 轴介导骨关节炎软骨中 FGF2 诱导的 ADAMTS 表达
DOI：
10.1007/s00109-016-1380-9
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发表时间：
2016-06-01
影响因子：
4.7
通讯作者：
Wang, Yan
中科院分区：
文献类型：
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作者：
Ji, Quanbo;Xu, Xiaojie;Wang, Yan
成纤维细胞生长因子2(FGF2)通过调节软骨降解在骨性关节炎(OA)的发生发展中起重要作用。然而，FGF2诱导骨性关节炎的分子机制尚不清楚。MicroRNAs(MiRNAs)维持软骨的动态平衡。为了验证FGF2是否通过对miRNA的调节来调节OA，我们利用微阵列分析筛选出了可以通过FGF2调节的潜在miRNA分子。结果表明，在FGF2刺激的软骨细胞中，microRNA-105(miR-105)的表达显著下调。Runt相关转录因子2(Runx2)是参与骨性关节炎的关键转录因子，已被确定为miR-105的新的潜在靶点。FGF2通过将核因子kappa B转录复合体p65的亚单位募集到miR-105启动子来抑制miR-105的表达。Runx2基因的敲除模仿了miR-105的作用，并取消了miR-105与凝血酶反应蛋白4(ADAMTS4)、ADAMTS5、ADAMTS7和ADAMTS12共同调节去整合素样和金属蛋白酶的表达的能力，这四种蛋白都参与了2A1胶原蛋白(COL2A1)和聚集素(Acan)的降解。MIR-105也是FGF2/P65诱导的Runx2激活和ADAMTS表达所必需的。此外，在骨性关节炎患者中miR-105表达下调，并与骨性关节炎患者中上调的Runx2、ADAMTS7和ADAMTS12的表达呈负相关。这些数据表明，FGF2/p65/miR-105/Runx2/ADAMTS轴可能在OA的发病机制中发挥重要作用，miR-105可能是一个潜在的诊断靶点和治疗OA的有用策略。关键信息Runx2被确定为一个新的直接靶点miR-105。FGF2通过招募p65到miR-105启动子来抑制miR-105的转录。p65/miR-105是FGF2介导的Runx2和ADAMTS上调所必需的。miR-105在OA中下调，并与Runx2的表达呈负相关。
AbstractFibroblast growth factor 2 (FGF2) plays an important role in the development of osteoarthritis (OA) through the regulation of cartilage degradation. However, the molecular mechanism underlying FGF2-induced OA is poorly characterized. MicroRNAs (miRNAs) maintain cartilage homeostasis. To examine whether FGF2 regulates OA through the modulation of miRNA, we screened potential miRNA molecules that could be regulated through FGF2 using microarray analysis. The results showed that microRNA-105 (miR-105) was significantly downregulated in chondrocytes stimulated with FGF2. Runt-related transcription factor 2 (Runx2), a key transcription factor involved in OA, has been identified as a novel potential target of miR-105. FGF2 suppressed miR-105 expression through the recruitment of the subunit of the nuclear factor kappa B transcription complex p65 to the miR-105 promoter. The knockdown of Runx2 mimicked the effect of miR-105 and abolished the ability of miR-105 to regulate the expression of a disintegrin-like and metalloproteinase with thrombospondin 4 (ADAMTS4), ADAMTS5, ADAMTS7 and ADAMTS12, both of which are responsible for the degradation of collagen 2A1 (COL2A1) and aggrecan (ACAN). miR-105 is also required for FGF2/p65-induced Runx2 activation and ADAMTS expression. Moreover, miR-105 expression was downregulated in OA patients and inversely correlated with the expression of Runx2, ADAMTS7 and ADAMTS12, which were upregulated in OA patients. These data highlight that the FGF2/p65/miR-105/Runx2/ADAMTS axis might play an important role in OA pathogenesis and that miR-105 might be a potential diagnostic target and useful strategy for OA treatment.Key messageRunx2 was identified as a novel direct target of miR-105.FGF2 inhibits miR-105 transcription through recruitment of p65 to miR-105 promoter.p65/miR-105 is essential for FGF2-mediated Runx2 and ADAMTS upregulation.miR-105 is downregulated in OA and inversely correlated with Runx2 expression.