MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Abstract

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-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. Methods: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a 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-146a 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-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. Conclusion: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes

“…In addition, in our study, the IL-1β-induced suppression of miR-92a-3p was reversed with treatment of NF-κB and MAPK inhibitors. A similar negative regulation of ADAMTS-4/5 in chondrocytes by activated NF-κB and MAPKs via miRNAs has been reported previously [42][43][44][45][46], suggesting that miRNAs with similar functions in inflammation and degeneration may be regulated by a common set of catabolic pathways in chondrocytes, including NF-κB and MAPK.…”

MiR-146a Aggravates LPS-Induced Inflammatory Injury by Targeting CXCR4 in the Articular Chondrocytes

“…The expression pattern of miR-146a in cartilage from patients with OA has been identified that miR-146a was intensely expressed in low-grade OA cartilage, suggesting the potential role of miR-146a in OA cartilage pathogenesis [19]. Another investigation indicated that miR-146a could protect cartilage from degeneration in OA, as miR-146a overexpression inhibited hypoxia-induced autophagy in chondrocytes [20]. However the exact role of miR-146a in OA is still unclearly.…”

Mechanism of MicroRNA-146a/Notch2 Signaling Regulating IL-6 in Graves Ophthalmopathy

“…MiR-146a, a member of the class of miRNAs, has been found to participate in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), Osteoarthritis (OA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and GO [3, 9-13]. For instance, MiR-146a was reported to induce TNF-α production by targeting TNF-α/TNF receptor-associated factor 6 (TRAF6)/IL-1 receptor-associated kinase 1 (IRAK1) signaling in RA [14].…”