Roles And Mechanisms Of MicroRNA-146a Induced By Hypoxia Promote Chondrocytes Autophagy

Background/Aims: There have been many studies on the etiology of osteoarthritis(OA)with regard to the function of inflammatory cytokines,the process of cartilage degradation,the function of miR-146 a,hypoxia stimulation and autophagy in OA chondrocytes,but there have been no reports on the relationship between miR-146 a and autophagy in cartilage,especially under hypoxia.This study aimed to confirm the relationship of miR-146 a and autophagy in cartilage under hypoxia.Methods: Chondrocytes were treated by hypoxia gradients,and the main factors including HIF-1α,HIF-2α,miR-146 a and Bcl-2 and autophagy markers ULK-1,ATG-5 were detected by quantitative PCR(Q-PCR)and western blotting.The autophagy marker LC-3 was detected by immunofluorescence.The reciprocal effects between miR-146 a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection.Results: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146 a expression via HIF-1α,but not HIF-2α,while miR-146 a did not reversely affect HIF-1α.The autophagy induced by hypoxia through HIF-1α,miR-146 a and Bcl-2.Simply,hypoxia induced HIF-1α,and HIF-1α increased miR-146 a,but miR-146 a suppressed Bcl-2,an autophagy inhibitor.While Bcl-2 affected neither HIF-1α nor miR-146 a.The absence of both HIF-1α and miR-146 a or Bcl-2 over-expression inhibited hypoxia-induced autophagy.Conclusion: HIF-1α,miR-146 a and Bcl-2 play crucial roles during hypoxia-induced autophagy,Hypoxia,HIF-1α and miR-146 a promote chondrocytes autophagy via depressing Bcl-2.We conclude that miR-146 a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.