Hypoxia-inducible factor-2α Regulates Fas-mediated Chondrocyte Apoptosis During Osteoarthritic Cartilage Destruction

Cell Death Differ. 2012 Mar;19(3):440-50. doi: 10.1038/cdd.2011.111. Epub 2011 Aug 26.

Abstract

Apoptosis of articular chondrocytes is associated with the pathogenesis of osteoarthritis (OA). Recently, we demonstrated that hypoxia-inducible factor (HIF)-2α, encoded by Epas1, causes OA cartilage destruction by regulating the expression of various matrix-degrading enzymes. Here, we investigated the involvement of HIF-2α in chondrocyte apoptosis and OA cartilage destruction. HIF-2α levels in human and mouse OA chondrocytes were markedly elevated in association with increased apoptosis of articular chondrocytes. Overexpression or knockdown of HIF-2α alone did not cause chondrocyte apoptosis. However, HIF-2α expression markedly increased chondrocyte apoptosis in the presence of an agonistic anti-Fas (CD95) antibody. HIF-2α enhanced Fas expression and potentiated downstream signaling pathways, increasing the activity of initiator and executioner caspases. Overexpression of HIF-2α in mouse cartilage tissue, either by intra-articular injection of Epas1 adenovirus (Ad-Epas1) or in the context of chondrocyte-specific Epas1 transgenic mice, increased chondrocyte apoptosis and cartilage destruction. In contrast, chondrocyte-specific knockout of Epas1 in mice suppressed DMM (destabilization of the medial meniscus)-induced chondrocyte apoptosis and inhibited OA cartilage destruction. Moreover, Fas-deficient mice exhibited diminished chondrocyte apoptosis and OA cartilage destruction in response to Ad-Epas1 injection or DMM surgery. Taken together, our results demonstrate that HIF-2α potentiates Fas-mediated chondrocyte apoptosis, which is associated with OA cartilage destruction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cartilage / metabolism*
  • Cartilage / pathology
  • Cells, Cultured
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Gene Expression Regulation / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Osteoarthritis / genetics
  • Osteoarthritis / metabolism*
  • Osteoarthritis / pathology
  • Signal Transduction / genetics
  • fas Receptor / biosynthesis*
  • fas Receptor / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • FAS protein, human
  • Fas protein, mouse
  • fas Receptor
  • endothelial PAS domain-containing protein 1