RGD Reference Report - Hypoxia-inducible factor-2alpha regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. - Rat Genome Database

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Hypoxia-inducible factor-2alpha regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction.

Authors: Ryu, JH  Shin, Y  Huh, YH  Yang, S  Chun, CH  Chun, JS 
Citation: Ryu JH, etal., Cell Death Differ. 2012 Mar;19(3):440-50. doi: 10.1038/cdd.2011.111. Epub 2011 Aug 26.
RGD ID: 10395364
Pubmed: PMID:21869830   (View Abstract at PubMed)
PMCID: PMC3278727   (View Article at PubMed Central)
DOI: DOI:10.1038/cdd.2011.111   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
EPAS1Humanosteoarthritis  ISOEpas1 (Mus musculus) RGD 
Epas1Ratosteoarthritis  ISOEpas1 (Mus musculus) RGD 
Epas1Mouseosteoarthritis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Epas1  (endothelial PAS domain protein 1)

Genes (Mus musculus)
Epas1  (endothelial PAS domain protein 1)

Genes (Homo sapiens)
EPAS1  (endothelial PAS domain protein 1)


Additional Information