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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.

MicroRNA-145 attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via direct suppression of MKK4