Interleukin‐6 plays an essential role in hypoxia‐inducible factor 2α–induced experimental osteoarthritic cartilage destruction in mice

Objective Hypoxia‐inducible factor 2α (HIF‐2α) (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‐2α–mediated OA cartilage destruction in mice. Methods The expression of HIF‐2α, 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‐2α–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‐2α adenovirus (AdEpas1) intraarticularly in mice with or without IL‐6–neutralizing antibody. Results We found that Il6 is a direct target gene of HIF‐2α in articular chondrocytes. Both Epas1 and Il6 were up‐regulated in human and mouse OA cartilage, whereas HIF‐2α 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‐2α–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‐2α–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‐2α–induced experimental OA cartilage destruction in mice via regulation of Mmp3 and Mmp13 levels.