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

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

doi:10.1038/nm.2153

Cited by 527Osteoarthritis Treatment and MechanismsHip disorders and treatmentsProtease and Inhibitor Mechanisms

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

Yang, Siyoung, Kim, Jonghwan, Ryu, Je-Hwang, Oh, Hwanhee, Chun, Churl-Hong, Kim, Byoung Ju, Min, Byoung Hyun, Chun, Jang-Soo·2010·Nature Medicine

DOI 10.1038/nm.2153

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Abstract

Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha 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-2alpha 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-2alpha causes cartilage destruction by regulating crucial catabolic genes.

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HIF-2α is a catabolic transcription factor in the osteoarthritic process.
“The hypoxia-inducible factor-2alpha (HIF-2α, encoded by Epas1) is a catabolic transcription factor in the osteoarthritic process.”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [4]
HIF-2α directly induces chondrocyte expression of catabolic factors including MMPs, ADAMTS4, NOS-2 and PTGS-2.
“HIF-2α directly induces chondrocytes expression of genes encoding catabolic factors, such as matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS-2) and prostaglandin-endoperoxide synthase-2 [3,4].”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [4]
HIF-2α does not induce transcription of ADAMTS5.
“It is reported that HIF-2α (like IL-1β) does not induce transcription of ADAMTS5 [3,4].”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [4]
IL-1β and other inflammatory mediators promote activation of latent ADAMTS-5.
“Instead, IL-1β and certain other inflammatory mediators promote activation of latent ADAMTS-5, as does hypertrophic differentiation in chondrocytes [3,4].”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [4]
An imbalance between anabolic and catabolic factors within chondrocytes may cause osteoarthritic cartilage destruction.
“An imbalance between anabolic and catabolic factors within chondrocytes may cause osteoarthritic cartilage destruction [3-5].”
From Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage (2015) · cites this paper as [4]

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Authors: Yang, S., Kim, J., Ryu, J.-H., Oh, H., Chun, C.-H., Kim, B. J., Min, B. H., & Chun, J.-S.
Affiliations: Gwangju Institute of Science and Technology (KR)
Wonkwang University Hospital (KR)
Ajou University (KR)
Corresponding author: Chun, Jang-Soo
ORCID: Yang, Siyoung
Ryu, Je-Hwang
Oh, Hwanhee
Chun, Churl-Hong
Chun, Jang-Soo
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2010-05-23
Volume: 16
Issue: 6
Pages: 687-693
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm.2153
OpenAlex: W1995577585
Cited by: 527
References: 52
Citations by year: 2026: 23 · 2025: 17 · 2024: 35 · 2023: 33 · 2022: 35 · 2021: 37 · 2020: 37 · 2019: 35 · 2018: 20 · 2017: 33 · 2016: 39 · 2015: 43 · 2014: 39 · 2013: 34 · 2012: 28
FWCI: 22.08
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
AJOU Open Repository (Ajou University) (submittedVersion)
Topics: Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Health Sciences › Medicine › Surgery › Hip disorders and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: HIF-2α, EPAS1, osteoarthritis, cartilage destruction, chondrocytes, catabolic gene expression, matrix metalloproteinases, ADAMTS-4, nitric oxide synthase 2, cyclooxygenase-2, destabilization of the medial meniscus, collagenase-induced osteoarthritis, therapeutic target
MeSH terms: Endothelial PAS Domain-Containing Protein 1, Animals, Cartilage, Cyclic AMP Receptor Protein, Gene Expression Regulation, Genes, Humans, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Osteoarthritis, Rabbits, Transcription Factors, Collagenases, Chondrocytes, Mice, Basic Helix-Loop-Helix Proteins, Gene Knockdown Techniques

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

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