title: Interleukin-6 plays an essential role in hypoxia-inducible factor 2α-induced experimental osteoarthritic cartilage destruction in mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: School of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors: Je-Hwang
authors: JH
authors: Ryu
authors: Siyoung
authors: S
authors: Yang
authors: Youngnim
authors: Y
authors: Shin
authors: Jinseol
authors: J
authors: Rhee
authors: Churl-Hong
authors: CH
authors: Chun
authors: Jang-Soo
authors: JS
authors: Chun