Interleukin-6 Plays an Essential Role in Hypoxia-Inducible Factor 2α-Induced Experimental Osteoarthritic Cartilage Destruction in Mice

Objective. Hypoxia-inducible factor 2 alpha (HIF-2 alpha) (encoded by Epas1) causes osteoarthritic (OA) cartilage destruction by regulating the expression of catabolic factor genes. We undertook this study to explore the role of interleukin-6 (IL-6) in HIF-2 alpha-mediated OA cartilage destruction in mice. Methods. The expression of HIF-2 alpha, IL-6, and catabolic factors was determined at the messenger RNA and protein levels in primary culture mouse chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, HIF-2 alpha knockdown (Epas1(+/-)), and Il6(-/-)mice was caused by intraarticular injection of Epas1 adenovirus or destabilization of the medial meniscus. The role of IL-6 was determined by treating with recombinant IL-6 protein or by injecting HIF-2 alpha adenovirus (AdEpas1) intra-articularly in mice with or without IL-6-neutralizing antibody. Results. We found that Il6 is a direct target gene of HIF-2 alpha in articular chondrocytes. Both Epas1 and Il6 were up-regulated in human and mouse OA cartilage, whereas HIF-2 alpha knockdown in mice led to inhibition of both Il6 expression and cartilage destruction. Treatment with IL-6 enhanced Mmp3 and Mmp13 expression; conversely, Il6 knockdown inhibited HIF-2 alpha-induced up-regulation of Mmp3 and Mmp13. Injection of IL-6 protein into mouse knee joints triggered OA cartilage destruction, whereas IL-6 neutralization led to blocking of HIF-2 alpha-induced cartilage destruction with concomitant modulation of Mmp3 and Mmp13 expression. Moreover, Il6 knockout resulted in inhibition of AdEpas1-induced and destabilization of the medial meniscus-induced cartilage destruction as well as inhibition of Mmp3 and Mmp13 expression. Conclusion. Our findings indicate that IL-6 acts as a crucial mediator of HIF-2 alpha-induced experimental OA cartilage destruction in mice via regulation of Mmp3 and Mmp13 levels.