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- Title
Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction.
- Authors
Siyoung Yang; Jonghwan Kim; Je-Hwang Ryu; Hwanhee Oh; Churl-Hong Chun; Byoung Ju Kim; Byoung Hyun Min; Jang-Soo Chun
- Abstract
Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2α directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2α expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2α causes cartilage destruction by regulating crucial catabolic genes.
- Subjects
OSTEOARTHRITIS; CARTILAGE diseases; HYPOXEMIA; ARTICULAR cartilage; METALLOPROTEINASES; CARTILAGE cells
- Publication
Nature Medicine, 2010, Vol 16, Issue 6, p687
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.2153