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Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction

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.

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Figure 1: Regulatory mechanisms of Epas1 expression in articular chondrocytes.
Figure 2: Hif-2α regulates expression of MMP1, MMP3, MMP9, MMP12, MMP13, ADAMTS4, PTGS2 and NOS2 in chondrocytes as direct target genes.
Figure 3: HIF-2α is overexpressed in OA cartilage of humans and STR/ort mice.
Figure 4: Overexpression of Hif-2α triggers cartilage destruction.
Figure 5: Chondrocyte-specific Epas1-transgenic (TG) mice show spontaneous cartilage destruction.
Figure 6: Genetic deletion of one allele of Epas1 inhibits OA cartilage destruction.

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Acknowledgements

This work was supported by grants from the National Research Foundation of Korea (Cell Dynamics Research Center 2009-00631480 and 2009-0092210), the Korea Healthcare Technology research and development project (A084062), the Korea Research Foundation (KRF-2006-312-C00611) and the Bioimaging Research Center (Gwangju Institute of Science and Technology).

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S.Y. contributed to the writing of the manuscript and performed most of the experiments, except for the NO and PGE2 assays (performed by J.K.), the cartilage explants and synovitis experiments (performed by J.-H.R.) and immunofluorescence microscopy and subchondral bone assays (performed by H.O.). C.-H.C. provided and evaluated human cartilage samples. B.J.K. and B.H.M. performed microsurgery to induce DMM. J.-S.C. initiated and supervised the project and contributed to the writing of the manuscript.

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Correspondence to Jang-Soo Chun.

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The authors declare no competing financial interests.

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Yang, S., Kim, J., Ryu, JH. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 16, 687–693 (2010). https://doi.org/10.1038/nm.2153

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