| First Author | Ryu JH | Year | 2012 |
| Journal | Cell Death Differ | Volume | 19 |
| Issue | 3 | Pages | 440-50 |
| PubMed ID | 21869830 | Mgi Jnum | J:203615 |
| Mgi Id | MGI:5527528 | Doi | 10.1038/cdd.2011.111 |
| Citation | Ryu JH, et al. (2012) Hypoxia-inducible factor-2alpha regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ 19(3):440-50 |
| abstractText | Apoptosis of articular chondrocytes is associated with the pathogenesis of osteoarthritis (OA). Recently, we demonstrated that hypoxia-inducible factor (HIF)-2alpha, encoded by Epas1, causes OA cartilage destruction by regulating the expression of various matrix-degrading enzymes. Here, we investigated the involvement of HIF-2alpha in chondrocyte apoptosis and OA cartilage destruction. HIF-2alpha levels in human and mouse OA chondrocytes were markedly elevated in association with increased apoptosis of articular chondrocytes. Overexpression or knockdown of HIF-2alpha alone did not cause chondrocyte apoptosis. However, HIF-2alpha expression markedly increased chondrocyte apoptosis in the presence of an agonistic anti-Fas (CD95) antibody. HIF-2alpha enhanced Fas expression and potentiated downstream signaling pathways, increasing the activity of initiator and executioner caspases. Overexpression of HIF-2alpha 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-2alpha potentiates Fas-mediated chondrocyte apoptosis, which is associated with OA cartilage destruction. |
