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

Arthritis Rheum. 2011 Sep;63(9):2732-43. doi: 10.1002/art.30451.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cartilage / drug effects
  • Cartilage / metabolism*
  • Cartilage / pathology
  • Cells, Cultured
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism
  • Mice
  • Mice, Transgenic
  • Osteoarthritis / metabolism*
  • Osteoarthritis / pathology


  • Basic Helix-Loop-Helix Transcription Factors
  • Interleukin-6
  • endothelial PAS domain-containing protein 1
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3