期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 3, 页码 440-450出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.111
关键词
chondrocytes; apoptosis; Fas signaling; HIF-2 alpha; osteoarthritis
资金
- National Research Foundation of Korea [2010-0001619, 2010-0026293, 2010-0015783]
- Korea Healthcare Technology RD Project [A101793]
- Korea Health Promotion Institute [A101793] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2007-0056243, 2010-0026293, 2009-0071107] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Apoptosis of articular chondrocytes is associated with the pathogenesis of osteoarthritis (OA). Recently, we demonstrated that hypoxia-inducible factor (HIF)-2 alpha, encoded by Epas1, causes OA cartilage destruction by regulating the expression of various matrix-degrading enzymes. Here, we investigated the involvement of HIF-2 alpha in chondrocyte apoptosis and OA cartilage destruction. HIF-2 alpha levels in human and mouse OA chondrocytes were markedly elevated in association with increased apoptosis of articular chondrocytes. Overexpression or knockdown of HIF-2 alpha alone did not cause chondrocyte apoptosis. However, HIF-2 alpha expression markedly increased chondrocyte apoptosis in the presence of an agonistic anti-Fas (CD95) antibody. HIF-2 alpha enhanced Fas expression and potentiated downstream signaling pathways, increasing the activity of initiator and executioner caspases. Overexpression of HIF-2 alpha 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-2 alpha potentiates Fas-mediated chondrocyte apoptosis, which is associated with OA cartilage destruction. Cell Death and Differentiation (2012) 19, 440-450; doi: 10.1038/cdd.2011.111; published online 26 August 2011
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