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

Siyoung Yang; Jonghwan Kim; Je Hwang Ryu; Hwanhee Oh; Churl Hong Chun; Byoung Ju Kim; Byoung Hyun Min; Jang Soo Chun

doi:10.1038/nm.2153

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

Siyoung Yang, Jonghwan Kim, Je Hwang Ryu, Hwanhee Oh, Churl Hong Chun, Byoung Ju Kim, Byoung Hyun Min, Jang Soo Chun

Research output: Contribution to journal › Article › peer-review

476 Scopus citations

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 prostaglandinendoperoxide 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.

Original language	English
Pages (from-to)	687-693
Number of pages	7
Journal	Nature Medicine
Volume	16
Issue number	6
DOIs	https://doi.org/10.1038/nm.2153
State	Published - Jun 2010
Externally published	Yes

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@article{cebcf9390b134fb896b41d7123dd214a,

title = "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 prostaglandinendoperoxide 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.",

author = "Siyoung Yang and Jonghwan Kim and Ryu, \{Je Hwang\} and Hwanhee Oh and Chun, \{Churl Hong\} and Kim, \{Byoung Ju\} and Min, \{Byoung Hyun\} and Chun, \{Jang Soo\}",

year = "2010",

month = jun,

doi = "10.1038/nm.2153",

language = "English",

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AU - Yang, Siyoung

AU - Kim, Jonghwan

AU - Ryu, Je Hwang

AU - Oh, Hwanhee

AU - Chun, Churl Hong

AU - Kim, Byoung Ju

AU - Min, Byoung Hyun

AU - Chun, Jang Soo

PY - 2010/6

Y1 - 2010/6

N2 - 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 prostaglandinendoperoxide 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.

AB - 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 prostaglandinendoperoxide 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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DO - 10.1038/nm.2153

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SP - 687

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JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

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

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