title: Hypoxia-induced microRNA-146a represses Bcl-2 through Traf6/IRAK1 but not Smad4 to promote chondrocyte autophagy.
abstract: It has been shown that hypoxia stimulation promotes chondrocytes autophagy partly through HIF-1α, miR-146a and Bcl-2 progressively, and this mechanism represented the connection among hypoxia, miR-146a and autophagy, and provides a possible therapeutic strategy for osteoarthritis. However, the interaction between miR-146a and Bcl-2 is still unclear. Here in a hypoxic environment, we quantified the three reported miR-146a targets: two inflammation related targets Traf6, IRAK1; and the only reported target in chondrocytes Smad4. We confirmed the regulative function of miR-146a between hypoxia and these genes, and explored the Bcl-2 expression and autophagy level under extrinsic up-regulation of these three gene separately. All the three genes were down-regulated by hypoxia. Surprisingly, Traf6 and IRAK, but not the unique Smad4 in chondrocytes, were restored by antagomiR-146a. Both Ad-Traf6 and Ad-IRAK1 reinstated hypoxia or miR-146a repressed Bcl-2. However, Ad-Smad4 did not affect Bcl-2 in hypoxia or normoxia. The autophagy level showed a reverse variability compared to Bcl-2. Taken together, our results provided evidence that Smad4, the unique reported target for miR-146a in chondrocytes is unusually not involved in the chondrocytes autophagy, while the Traf6 and IRAK1 are the new targets for miR-146a in chondrocytes during autophagy.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Liu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zou
authors.forename: Tielong
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D019902:Chondrocytes / Q000473:pathology; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D051901:Smad4 Protein / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051901:Smad4 Protein; D048029:TNF Receptor-Associated Factor 6; D019938:Cyclin D1; D053592:Interleukin-1 Receptor-Associated Kinases