MicroRNA-145 attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via direct suppression of MKK4.
MicroRNA-145 attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via direct suppression of MKK4.
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MicroRNA-145 通过直接抑制 MKK4 减弱骨关节炎中 TNF-α 驱动的软骨基质降解
DOI：
10.1038/cddis.2017.522
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发表时间：
2017-10-26
影响因子：
9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Hu G;Zhao X;Wang C;Geng Y;Zhao J;Xu J;Zuo B;Zhao C;Wang C;Zhang X
骨关节炎（OA）的发病机制与软骨动态平衡障碍有关，肿瘤坏死因子（TNF）-α通过驱动炎症级联反应和软骨降解在OA发病过程中发挥重要作用。然而，TNF-α介导的信号传导的负调节仍然不确定。在这里，我们证明了miR-145在调节TNF-α介导的信号传导和软骨基质降解中的关键作用。TNF-α刺激软骨细胞的microRNA（miRNA）表达谱显示，miR-145表达被TNF-α迅速下调。此外，miR-145被p65直接抑制，并且在OA进展期间与TNF-α分泌呈负相关。此外，我们发现miR-145直接靶向丝裂原活化蛋白激酶激酶4（MKK 4），并广泛抑制几种TNF-α触发的基质降解酶（MMP-3，MMP-13和Adamts-5）的产生。机制研究显示，miR-145通过抑制MKK 4磷酸化，负性调节TNF-α介导的JNK和p38活化，以及p-c-Jun和p-ATF 2的核内积累，最终导致分解代谢基因转录的改变。事实上，p-ATF 2与Mmp-13的启动子相互作用，而p-c-Jun与Mmp-3和Adamts-5的启动子结合。MKK 4在OA软骨中显著升高。通过短发夹RNA消除MKK 4导致基质降解酶的产生明显减少，JNK和p38失活，并抑制软骨降解。相反，MKK 4过表达增强了TNF-α介导的信号激活和下游分解代谢基因的转录，从而加剧了软骨降解。此外，关节内（IA）注射miR-145激动剂至患有手术诱导的OA的大鼠减轻了软骨破坏。总之，我们阐明了TNF-α触发软骨降解的一种新的调控机制，并证明了miR-145和MKK 4作为OA治疗靶点的潜在效用。
Cartilage dyshomeostasis contributes to osteoarthritis (OA) pathogenesis, and tumor necrosis factor (TNF)-α has critical role in this process by driving inflammatory cascades and cartilage degradation. However, the negative regulation of TNF-α-mediated signaling remains undefined. Here we demonstrate the crucial role of miR-145 in the modulation of TNF-α-mediated signaling and cartilage matrix degradation. MicroRNA (miRNA) expression profiles of TNF-α-stimulated chondrocytes showed that miR-145 expression was rapidly downregulated by TNF-α. Moreover, miR-145 was directly repressed by p65 and was negatively correlated with TNF-α secretion during OA progression. Further, we found that miR-145 directly targeted mitogen-activated protein kinase kinase 4 (MKK4) and broadly restrained the production of several TNF-α-triggered matrix-degrading enzymes (MMP-3, MMP-13, and Adamts-5). Mechanistic studies unveiled that miR-145 negatively regulated TNF-α-mediated JNK and p38 activation, as well as the nuclear accumulation of p-c-Jun and p-ATF2, by inhibiting MKK4 phosphorylation, eventually resulting in the alteration of catabolic genes transcription. Indeed, p-ATF2 interacted with the promoter of Mmp-13, whereas p-c-Jun bound to promoters of Mmp-3 and Adamts-5. MKK4 was significantly elevated in OA cartilage. Eliminating MKK4 by short hairpin RNA resulted in obviously decreased matrix-degrading enzymes production, JNK and p38 inactivation, and an inhibition of cartilage degradation. On the contrary, MKK4 overexpression enhanced TNF-α-mediated signaling activation and transcription of downstream catabolic genes, and consequently worsened cartilage degradation. Moreover, intra-articular (IA) injection of miR-145 agonist to rat with surgery-induced OA alleviated cartilage destruction. Altogether, we elucidate a novel regulatory mechanism underlying TNF-α-triggered cartilage degradation and demonstrate the potential utility of miR-145 and MKK4 as therapy targets for OA.
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