Transcriptional Regulation of Endochondral Ossification by HIF-2alpha During Skeletal Growth and Osteoarthritis Development

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2010 May 25

PMID 20495570

Citations 268

Authors

Taku Saito

Atsushi Fukai

Akihiko Mabuchi

Toshiyuki Ikeda

Fumiko Yano

Shinsuke Ohba

Nao Nishida

Toru Akune

Noriko Yoshimura

Takumi Nakagawa

Kozo Nakamura

Katsushi Tokunaga

Ung-Il Chung

Hiroshi Kawaguchi

Affiliations

Soon will be listed here.

Abstract

Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.

Citing Articles

Single-cell RNA sequencing generates an atlas of normal tibia cartilage under mechanical loading conditions.

Wang J, Sun Z, Yu C, Zhao H, Yan M, Sun S Mol Cell Biochem. 2025; .

PMID: 40072674 DOI: 10.1007/s11010-025-05234-x.

Alternatively spliced NFKB1 transcripts enriched in Andean Aymara modulate inflammation, HIF and hemoglobin.

Song J, Han S, Amaru R, Lanikova L, Quispe T, Kim D Nat Commun. 2025; 16(1):1766.

PMID: 39971917 PMC: 11840074. DOI: 10.1038/s41467-025-56848-0.

Targeting Chondrocyte Hypertrophy as Strategies for the Treatment of Osteoarthritis.

Dong D, Jin G Bioengineering (Basel). 2025; 12(1).

PMID: 39851351 PMC: 11760869. DOI: 10.3390/bioengineering12010077.

Single-cell RNA sequencing identifies the expression of hemoglobin in chondrocyte cell subpopulations in osteoarthritis.

Zhang Z, He T, Gu H, Zhao Y, Tang S, Han K BMC Mol Cell Biol. 2024; 25(1):28.

PMID: 39736555 PMC: 11687149. DOI: 10.1186/s12860-024-00519-3.

A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification.

Ferrao Blanco M, Lesage R, Kops N, Fahy N, Bekedam F, Chavli A Heliyon. 2024; 10(23):e40871.

PMID: 39717596 PMC: 11664402. DOI: 10.1016/j.heliyon.2024.e40871.

References

Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z . Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 2006; 54(8):2462-70. DOI: 10.1002/art.22041. View

Zelzer E, Mamluk R, Ferrara N, Johnson R, Schipani E, Olsen B . VEGFA is necessary for chondrocyte survival during bone development. Development. 2004; 131(9):2161-71. DOI: 10.1242/dev.01053. View

Schofield C, Ratcliffe P . Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004; 5(5):343-54. DOI: 10.1038/nrm1366. View

Kronenberg H . Developmental regulation of the growth plate. Nature. 2003; 423(6937):332-6. DOI: 10.1038/nature01657. View

OROURKE J, Tian Y, Ratcliffe P, Pugh C . Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha. J Biol Chem. 1999; 274(4):2060-71. DOI: 10.1074/jbc.274.4.2060. View

Kuhn K, DLima D, Hashimoto S, Lotz M . Cell death in cartilage. Osteoarthritis Cartilage. 2003; 12(1):1-16. DOI: 10.1016/j.joca.2003.09.015. View

Hirata M, Kugimiya F, Fukai A, Ohba S, Kawamura N, Ogasawara T . C/EBPbeta Promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57. PLoS One. 2009; 4(2):e4543. PMC: 2638010. DOI: 10.1371/journal.pone.0004543. View

Maemura K, HSIEH C, Jain M, Fukumoto S, Layne M, Liu Y . Generation of a dominant-negative mutant of endothelial PAS domain protein 1 by deletion of a potent C-terminal transactivation domain. J Biol Chem. 1999; 274(44):31565-70. DOI: 10.1074/jbc.274.44.31565. View

Patel S, Simon M . Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ. 2008; 15(4):628-34. PMC: 2882207. DOI: 10.1038/cdd.2008.17. View

10.

Lando D, Peet D, Whelan D, Gorman J, Whitelaw M . Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002; 295(5556):858-61. DOI: 10.1126/science.1068592. View

11.

Stewart A, Houston B, Farquharson C . Elevated expression of hypoxia inducible factor-2alpha in terminally differentiating growth plate chondrocytes. J Cell Physiol. 2005; 206(2):435-40. DOI: 10.1002/jcp.20481. View

12.

Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M . Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol. 2001; 153(1):87-100. PMC: 2185519. DOI: 10.1083/jcb.153.1.87. View

13.

Bohensky J, Terkhorn S, Freeman T, Adams C, Garcia J, Shapiro I . Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy. Arthritis Rheum. 2009; 60(5):1406-15. PMC: 2747039. DOI: 10.1002/art.24444. View

14.

Iliopoulos D, Malizos K, Oikonomou P, Tsezou A . Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS One. 2008; 3(11):e3740. PMC: 2582945. DOI: 10.1371/journal.pone.0003740. View

15.

Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T . Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage. 2005; 13(7):632-41. DOI: 10.1016/j.joca.2005.03.004. View

16.

Miyagishi M, Taira K . RNAi expression vectors in mammalian cells. Methods Mol Biol. 2004; 252:483-91. DOI: 10.1385/1-59259-746-7:483. View

17.

Jain S, Maltepe E, Lu M, Simon C, Bradfield C . Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev. 1998; 73(1):117-23. DOI: 10.1016/s0925-4773(98)00038-0. View

18.

Pritzker K, Gay S, Jimenez S, Ostergaard K, Pelletier J, Revell P . Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. 2005; 14(1):13-29. DOI: 10.1016/j.joca.2005.07.014. View

19.

Semenza G . HIF-1 and human disease: one highly involved factor. Genes Dev. 2000; 14(16):1983-91. View

20.

Muraki S, Oka H, Akune T, Mabuchi A, En-Yo Y, Yoshida M . Prevalence of radiographic knee osteoarthritis and its association with knee pain in the elderly of Japanese population-based cohorts: the ROAD study. Osteoarthritis Cartilage. 2009; 17(9):1137-43. DOI: 10.1016/j.joca.2009.04.005. View