Hypoxia-inducible factor-2α regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction
Open accessAbstract
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.
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A stress-induced increase in HIF-2α activity overshadows HIF-1α and drives osteoarthritis changes.
“According to this paradigm, a stress-induced increase in the activity of HIF-2α will overshadow the beneficial effects of the closely related HIF-1α, then push the chondrocytes in the joint toward a more differentiated state known as hypertrophy, which then drives osteoarthritis changes [6,7].”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [7]
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- Authors
- Ryu, J.-H., Shin, Y., Huh, Y. H., Yang, S., Chun, C.-H., & Chun, J.-S.
- Affiliations
- Gwangju Institute of Science and Technology (KR)
- Wonkwang University Hospital (KR)
- Corresponding author
- Chun, J-S
- Venue
- Cell Death & Differentiation
- Published
- 2011-08-26
- Volume
- 19
- Issue
- 3
- Pages
- 440-450
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3278727
- OpenAlex
- W1971564704
- Cited by
- 123
- References
- 39
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 13 · 2023: 14 · 2022: 8 · 2021: 13 · 2020: 11 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 14 · 2014: 10 · 2013: 4 · 2012: 2
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Surgery › Hip disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- HIF-2α, EPAS1, Fas, chondrocyte apoptosis, osteoarthritis, cartilage destruction, caspase activation, destabilization of the medial meniscus, Fas-deficient mice, articular cartilage
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cartilage, Cells, Cultured, Gene Expression Regulation, Humans, Mice, Transgenic, Osteoarthritis, Signal Transduction, Apoptosis, fas Receptor, Chondrocytes, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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