<p>TMF inhibits miR-29a/Wnt/β-catenin signaling through upregulating Foxo3a activity in osteoarthritis chondrocytes</p>

Abstract

Background: miR-29a, a downstream factor of Wnt/β-catenin signaling, promotes the activity of the Wnt/β-catenin signaling in a positive feedback loop. Our previous work showed that 5,7,3ʹ,4ʹ-tetramethoxyflavone (TMF), a major constituent from Murraya exotica L., exhibited chondroprotective activity by inhibiting the activity of Wnt/β-catenin signaling. Purpose: To investigate whether TMF showed the inhibitory effects on miR-29a/β-catenin signaling by up regulation of Foxo3a expression. Methods: Rat knee OA models were duplicated by using Hulth’s method. TMF (5 μg/mL and 20 μg/mL) was used for administration to cultured cells, which were isolated from the rat cartilages. Analysis of chondrocytes apoptosis, gene expression, and protein expression were conducted. In addition, miR-29a mimics and pcDNA3.1(+)-Foxo3a vector were used for transfection, luciferase reporter assay for detecting the activity of Wnt/β-catenin signaling, and co-immunoprecipitation for determining proteins interaction. Results: TMF down regulated miR-29a/β-catenin signaling activity and cleaved caspase-3 expression and up regulated Foxo3a expression in OA rat cartilages. In vitro, miR-29a mimics down regulated the expression of Foxo3a and up regulated the activity of Wnt/β-catenin signaling and cleaved caspase-3 expression. TMF ameliorated miR-29a/β-catenin-induced chondrocytes apoptosis by up regulation of Foxo3a expression. Conclusion: TMF exhibited chondroprotective activity by up regulating Foxo3a expression and subsequently inhibiting miR-29a/Wnt/β-catenin signaling activity.

Hydrostatic Pressure Regulates Oxidative Stress through microRNA in Human Osteoarthritic Chondrocytes

“…We further hypothesize that the effect of mechanical loading or, specifically, of HP on Wnt/β-catenin pathway could be mediated by miRNA. Indeed, several investigations demonstrated, in human and rat OA chondrocyte cultures, the direct targeting of some miRNA, implicated in OA damage, on Wnt or β-catenin proteins [70][71][72][73]. Likewise, our data reported a reduced β-catenin protein expression when OA chondrocytes were transiently silenced with miR-34a specific inhibitor; moreover, miRNA inhibition limited the negative effects of overloading HP on β-catenin expression and enhanced, even if not significantly, those of low cyclic pressure.…”

Molecular mechanisms of mechanical load-induced osteoarthritis

“…Excessive Wnt signal levels upregulates ADAMT4, ADAMT5, ADAMT7, and ADAMT12 and promotes the degradation of ECM. However, IWP-2 (a Wnt signaling inhibitor) suppresses overloading-induced chondrocyte catabolism [46].…”

Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis

“…It diminishes the IL-1β-induced production of NO, PGE2, TNF-α, MMP-2, MMP-3, MMP-8, and MMP-9; downregulates the expression of COX-2, iNOS, MMP-1, MMP-3, MM-13, ADAMTS-4, and ADAMTS-5; inhibits the degradation of collagen type II [ 83 , 84 , 85 ]. Luteolin also protects chondrocytes from apoptosis by increasing Foxo3a expression via regulating the IRE1α pathway and miR-29a/Wnt/β-catenin signaling [ 86 , 87 ]. Its administration can also attenuate cartilage degradation and increase collagen type II expression in OA rats in vivo [ 83 ].…”