Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development
Open accessAbstract
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.
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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 [3]
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 [3]
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 [3]
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 [3]
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 [3]
Cites
Radiological Assessment of Osteo-Arthrosis
Kellgren, J., & Lawrence, J. S. (1957) · Annals of the Rheumatic Diseases · doi:10.1136/ard.16.4.494 · Cited by 12,472 · see citing works
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650020617 · Cited by 5,015 · see citing works
NF-κB regulation in the immune system
Li, Q., & Verma, I. M. (2002) · Nature Reviews Immunology · doi:10.1038/nri910 · Cited by 4,007 · see citing works
Bone Histomorphometry : Standardization of Nomenclature, Symbols, and Units
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · Cited by 3,258 · see citing works
Developmental regulation of the growth plate
Kronenberg, H. M. (2003) · Nature · doi:10.1038/nature01657 · Cited by 2,859 · see citing works
Osteoarthritis cartilage histopathology: grading and staging
Pritzker, K. P. H., Gay, S., Jiménez, S. A., Østergaard, K., Pelletier, J., Revell, P. A., Salter, D. M., & van den Berg, W. B. (2005) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2005.07.014 · Cited by 2,355 · see citing works
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
Biochemical and Metabolic Abnormalities in Articular Cartilage from Osteo-Arthritic Human Hips
Mankin, H. J., DORFMAN, H., Lippiello, L., & Zarins, A. (1971) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-197153030-00009 · Cited by 1,969 · see citing works
Charalambous, C. P. (2013) · Springer eBooks · doi:10.1007/978-1-4471-5451-8_97 · Cited by 1,845 · see citing works
Plat-E: an efficient and stable system for transient packaging of retroviruses
MORITA, S., Kojima, T., & Kitamura, T. (2000) · Gene Therapy · doi:10.1038/sj.gt.3301206 · Cited by 1,660 · see citing works
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · see citing works
Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis
Glasson, S. S., Askew, R., Sheppard, B. J., Carito, B. A., Blanchet, T., Ma, H., Flannery, C. R., Peluso, D., Kanki, K., Yang, Z., et al. (2005) · Nature · doi:10.1038/nature03369 · Cited by 1,258 · see citing works
ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro
Stanton, H., Rogerson, F. M., East, C. J., Golub, S. B., Lawlor, K. E., Meeker, C. T., Little, C. B., Last, K., Farmer, P. J., Campbell, I. K., et al. (2005) · Nature · doi:10.1038/nature03417 · Cited by 920 · see citing works
HIF-1 and human disease: one highly involved factor
Semenza, G. L. (2000) · Genes & Development · doi:10.1101/gad.14.16.1983 · Cited by 909 · see citing works
Biochemical and Metabolic Abnormalities in Articular Cartilage from Osteo-Arthritic Human Hips
Mankin, H. J., & Lippiello, L. (1970) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-197052030-00002 · Cited by 854 · see citing works
Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survivalPreprint
Schipani, E., Ryan, H. E., Didrickson, S., Kobayashi, T., Knight, M. C., & Johnson, R. S. (2001) · Genes & Development · doi:10.1101/gad.934301 · Cited by 812 · see citing works
Mankin, H. J., Dorfman, H., Lippiello, L., & Zarins, A. (1971) · PubMed · Cited by 796 · see citing works
Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W., & McKnight, S. L. (1998) · Genes & Development · doi:10.1101/gad.12.21.3320 · Cited by 647 · see citing works
Little, C. B., Barai, A., Burkhardt, D., Smith, S. M., Fosang, A. J., Werb, Z., Shah, M., & Thompson, E. W. (2009) · Arthritis & Rheumatism · doi:10.1002/art.25002 · Cited by 642 · see citing works
Altered endochondral bone development in matrix metalloproteinase 13-deficient mice
Stickens, D., Behonick, D. J., Ortéga, N., Heyer, B. S., Hartenstein, B., Yu, Y., Fosang, A., Schorpp‐Kistner, M., Angel, P. E., & Werb, Z. (2004) · Development · doi:10.1242/dev.01461 · Cited by 608 · see citing works
Osteoarthritis development in novel experimental mouse models induced by knee joint instability
Kamekura, S., Hoshi, K., Shimoaka, T., Chung, U., Chikuda, H., Yamada, T., Uchida, M., Ogata, N., Seichi, A., Nakamura, K., et al. (2005) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2005.03.004 · Cited by 583 · see citing works
Self-citationIliopoulos, D., Malizos, K., Oikonomou, P., & Tsezou, A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003740 · Cited by 501 · see citing works
Scortegagna, M., Ding, K., Oktay, Y., Gaur, A., Thurmond, F., Yan, L.-J., Marck, B. T., Matsumoto, A. M., Shelton, J. M., Richardson, J. A., et al. (2003) · Nature Genetics · doi:10.1038/ng1266 · Cited by 496 · see citing works
Matrix remodeling during endochondral ossification
Ortéga, N., Behonick, D. J., & Werb, Z. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.12.003 · Cited by 463 · see citing works
MEF2C Transcription Factor Controls Chondrocyte Hypertrophy and Bone Development
Arnold, M., Kim, Y., Czubryt, M. P., Phan, D., McAnally, J., Qi, X., Shelton, J. M., Richardson, J. A., Bassel‐Duby, R., & Olson, E. N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.02.004 · Cited by 456 · see citing works
Muraki, S., Oka, H., Akune, T., et al. (2009) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2009.04.005 · Cited by 437 · see citing works
Self-citationVEGFA is necessary for chondrocyte survival during bone development
Zelzer, E., Mamluk, R., Ferrara, N., Johnson, R. S., Schipani, E., & Olsen, B. R. (2004) · Development · doi:10.1242/dev.01053 · Cited by 401 · see citing works
Ueta, C., Iwamoto, M., Kanatani, N., Yoshida, C. A., Liu, Y., Enomoto‐Iwamoto, M., Ohmori, T., Enomoto, H., Nakata, K., Takada, K., et al. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.1.87 · Cited by 367 · see citing works
Expression of ARNT, ARNT2, HIF1α, HIF2α and Ah receptor mRNAs in the developing mouse
Jain, S., Maltepe, E., Lu, M. M., Simon, C., & Bradfield, C. A. (1998) · Mechanisms of Development · doi:10.1016/s0925-4773(98)00038-0 · Cited by 333 · see citing works
Regulation of skeletal development by the Runx family of transcription factors
Komori, T. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20420 · Cited by 330 · see citing works
Biology of hypoxia-inducible factor-2α in development and disease
Patel, S. A., & Simon, M. C. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.17 · Cited by 325 · see citing works
Kamekura, S., Kawasaki, Y., Hoshi, K., Shimoaka, T., Chikuda, H., Maruyama, Z., Komori, T., Sato, S., Takeda, S., Karsenty, G., et al. (2006) · Arthritis & Rheumatism · doi:10.1002/art.22041 · Cited by 319 · see citing works
Self-citationSyndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis
Echtermeyer, F. G., Bertrand, J., Dreier, R., Meinecke, I., Neugebauer, K., Fuerst, M. E., Lee, Y. J., Song, Y. W., Herzog, C., Theilmeier, G., et al. (2009) · Nature Medicine · doi:10.1038/nm.1998 · Cited by 318 · see citing works
Amarilio, R., Viukov, S. V., Sharir, A., Eshkar-Oren, I., Johnson, R. S., & Zelzer, E. (2007) · Development · doi:10.1242/dev.008441 · Cited by 317 · see citing works
Kühn, K., DʼLima, D. D., Hashimoto, S., & Lotz, M. (2003) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2003.09.015 · Cited by 317 · see citing works
Modulating hedgehog signaling can attenuate the severity of osteoarthritis
Lin, A. C., Seeto, B. L., Bartoszko, J. M., et al. (2009) · Nature Medicine · doi:10.1038/nm.2055 · Cited by 316 · see citing works
HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes
Pfander, D., Cramer, T., Schipani, E., & Johnson, R. S. (2003) · Journal of Cell Science · doi:10.1242/jcs.00385 · Cited by 261 · see citing works
O'Rourke, J. F., Tian, Y.-M., Ratcliffe, P. J., & Pugh, C. W. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.4.2060 · Cited by 242 · see citing works
Pescador, N., Cuevas, Y., Suárez, S. N., Alcaide, M., Villar, D., Landázuri, M. O., & del Peso, L. (2005) · Biochemical Journal · doi:10.1042/bj20042121 · Cited by 240 · see citing works
Kwan, K. M., Pang, M. K. M., Zhou, S. X., Cowan, S., Kong, R. Y. C., Pfordte, T., Olsen, B. R., Sillence, D. O., Tam, P., & Cheah, K. S. E. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.136.2.459 · Cited by 200 · see citing works
Kawaguchi, H. (2008) · Molecules and Cells · doi:10.1016/s1016-8478(23)17544-3 · Cited by 149 · see citing works
Self-citationNormal long bone growth and development in type X collagen-null mice
Rosati, R., Horan, G. S. B., Pinero, G. J., et al. (1994) · Nature Genetics · doi:10.1038/ng1094-129 · Cited by 148 · see citing works
Bohensky, J., Terkhorn, S. P., Freeman, T. A., Adams, C. S., Garcia, J. A., Shapiro, I. M., & Srinivas, V. (2009) · Arthritis & Rheumatism · doi:10.1002/art.24444 · Cited by 135 · see citing works
New experimental approaches in retrovirus-mediated expression screening.
Kitamura (1998) · International Journal of Hematology · doi:10.1016/s0925-5710(98)00025-5 · Cited by 126 · see citing works
Drissi, H., Zuscik, M. J., Rosier, R. N., & O’Keefe, R. J. (2005) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2005.01.003 · Cited by 118 · see citing works
Validity of histopathological grading of articular cartilage from osteoarthritic knee joints
Østergaard, K., Andersen, C. B., Petersen, J. H., Bendtzen, K., & Salter, D. M. (1999) · Annals of the Rheumatic Diseases · doi:10.1136/ard.58.4.208 · Cited by 109 · see citing works
Saito, T., Ikeda, T., Nakamura, K., Chung, U., & Kawaguchi, H. (2007) · EMBO Reports · doi:10.1038/sj.embor.7400934 · Cited by 105 · see citing works
Self-citationHirata, M., Kugimiya, F., Fukai, A., Ohba, S., Kawamura, N., Ogasawara, T., Kawasaki, Y., Saito, T., Yano, F., Ikeda, T., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004543 · Cited by 91 · see citing works
Self-citationGrowth Plate Compressions and Altered Hematopoiesis in Collagen X Null Mice
Gress, C. J., & Jacenko, O. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.4.983 · Cited by 70 · see citing works
Autophagy in mineralizing tissues: Microenvironmental perspectives
Srinivas, V., Bohensky, J., Zahm, A. M., & Shapiro, I. M. (2009) · Cell Cycle · doi:10.4161/cc.8.3.7545 · Cited by 64 · see citing works
Hypoxia and HIF‐1α in Chondrogenesis
Schipani, E. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1346.009 · Cited by 62 · see citing works
Carminerin contributes to chondrocyte calcification during endochondral ossification
Yamada, T., Kawano, H., Koshizuka, Y., Fukuda, T., Yoshimura, K., Kamekura, S., Saito, T., Ikeda, T., Kawasaki, Y., Azuma, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1409 · Cited by 59 · see citing works
Self-citationMaemura, K., Hsieh, C.-M., Jain, M. K., Fukumoto, S., Layne, M. D., Liu, Y., Kourembanas, S., Yet, S., Perrella, M. A., & Lee, M.-E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.44.31565 · Cited by 57 · see citing works
Tamiya, H., Ikeda, T., Jeong, J., Saito, T., Yano, F., Jung, Y., Ohba, S., Kawaguchi, H., Chung, U., & Choi, J. (2008) · Gene · doi:10.1016/j.gene.2008.03.003 · Cited by 45 · see citing works
Self-citationMagee, C., Nurminskaya, M., Faverman, L., Galéra, P., & Linsenmayer, T. F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412549200 · Cited by 41 · see citing works
Stewart, A. J., Houston, B., & Farquharson, C. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20481 · Cited by 36 · see citing works
RNAi Expression Vectors in Mammalian Cells
Miyagishi, M., & Taira, K. (2004) · Humana Press eBooks · doi:10.1385/1-59259-746-7:483 · Cited by 28 · see citing works
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Koh, M. Y., & Powis, G. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.06.004 · Cited by 589 · see citing works
Philipot, D., Guérit, D., Platano, D., Chuchana, P., Olivotto, E., Espinoza, F., Dorandeu, A., Pers, Y.-M., Piette, J., Borzi, R. M., et al. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4494 · Cited by 226 · see citing works
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Ruan, M. Z. C., Erez, A., Guse, K., Dawson, B., Bertin, T., Chen, Y., Jiang, M.-M., Yustein, J., Gannon, F., & Lee, B. H. L. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005409 · Cited by 196 · see citing works
Sheu, S.-Y., Ho, S.-R., Sun, J.-S., Chen, C.-Y., & Ke, C.-J. (2015) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-015-0520-z · Cited by 181 · see citing works
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Shapiro, I. M., Layfield, R., Lotz, M., Settembre, C., & Whitehouse, C. (2014) · Autophagy · doi:10.4161/auto.26679 · Cited by 175 · see citing works
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- Authors
- Saito, T., Fukai, A., Mabuchi, A., Ikeda, T., Yano, F., Ohba, S., Nishida, N., Akune, T., Yoshimura, N., Nakagawa, T., Nakamura, K., Tokunaga, K., Chung, U.-I., & Kawaguchi, H.
- Affiliations
- The University of Tokyo (JP)
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- Corresponding author
- Kawaguchi, Hiroshi
- ORCID
- Venue
- Nature Medicine
- Published
- 2010-05-23
- Volume
- 16
- Issue
- 6
- Pages
- 678-686
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1975554070
- Cited by
- 532
- References
- 57
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 22 · 2023: 25 · 2022: 33 · 2021: 54 · 2020: 48 · 2019: 35 · 2018: 26 · 2017: 30 · 2016: 35 · 2015: 42 · 2014: 38 · 2013: 33 · 2012: 26
- FWCI
- 22.08
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (21390417, 22689052)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Surgery › Hip disorders and treatments
- Keywords
- HIF-2α, EPAS1, osteoarthritis, endochondral ossification, chondrocyte hypertrophy, COL10A1, MMP-13, VEGF-A, hypoxia response element, transcriptional regulation, RelA, NF-κB, single nucleotide polymorphisms, therapeutic target, skeletal development
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Aged, Aged, 80 and over, Animals, Bone Development, Cells, Cultured, Humans, Mice, Mutant Strains, Middle Aged, Osteoarthritis, Osteogenesis, Transcription, Genetic, Trans-Activators, Case-Control Studies, Gene Expression Regulation, Developmental, Chondrocytes, Osteoarthritis, Knee, Collagen Type X, Mice, Basic Helix-Loop-Helix Proteins
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