Abstract
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.
Highlights
Osteoarthritis (OA) is the most prevalent chronic joint disease characterized by a group of abnormalities, such as cartilage destruction, subchondral bone remodeling, and synovial inflammation.[1]
It is known that inflammation presents cascade amplification,[8] implying that signaling cascades consisting of protein kinases, especially the upstream molecules involved in NF-κB and mitogen-activated protein kinases (MAPK) signaling pathways, may have vital roles in driving the inflammatory cascade during OA
As the main cytokines involved in OA pathogenesis, IL-1β is mainly associated with cartilage destruction, whereas TNF-α is implicated in driving of the inflammatory cascades during OA.[4,9]
Summary
Osteoarthritis (OA) is the most prevalent chronic joint disease characterized by a group of abnormalities, such as cartilage destruction, subchondral bone remodeling, and synovial inflammation.[1]. RIP1 in turn recruits TNF receptor associated factor-2 (TRAF2) and/or TRAF5, as well as cellular inhibitor of apoptosis protein-1 (cIAP1) and cIAP2. These adaptors act in concert with RIP1 to engage the downstream phosphorylation cascades to activate NF-κB, JNK, and p38 pathways, which promote inflammation and transcriptional activation.[13,14,15] the negative regulation of TNF-α-mediated signal transduction, especially the modulation of upstream molecules still remains largely unknown. MiR-145 suppresses TNF-α-mediated JNK/c-Jun and p38/ATF2 activation and induction of MMP-3, MMP-13, and Adamts-5 by directly targeting mitogenactivated protein kinase kinase 4 (MKK4), and attenuates cartilage matrix degradation in experimental OA
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