title: Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disorder that manifests as chronic inflammation and joint tissue destruction. However, the etiology and pathogenesis of RA have not been fully elucidated. Here, we explored the role of the hypoxia-inducible factors (HIFs), HIF-1α (encoded by HIF1A) and HIF-2α (encoded by EPAS1). HIF-2α was markedly up-regulated in the intimal lining of RA synovium, whereas HIF-1α was detected in a few cells in the sublining and deep layer of RA synovium. Overexpression of HIF-2α in joint tissues caused an RA-like phenotype, whereas HIF-1α did not affect joint architecture. Moreover, a HIF-2α deficiency in mice blunted the development of experimental RA. HIF-2α was expressed mainly in fibroblast-like synoviocytes (FLS) of RA synovium and regulated their proliferation, expression of RANKL (receptor activator of nuclear factor-κB ligand) and various catabolic factors, and osteoclastogenic potential. Moreover, HIF-2α-dependent up-regulation of interleukin (IL)-6 in FLS stimulated differentiation of TH17 cells-crucial effectors of RA pathogenesis. Additionally, in the absence of IL-6 (Il6-/- mice), overexpression of HIF-2α in joint tissues did not cause an RA phenotype. Thus, our results collectively suggest that HIF-2α plays a pivotal role in the pathogenesis of RA by regulating FLS functions, independent of HIF-1α.
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea; Research Center for Biomineralization Disorders and Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Je-Hwang
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Chang-Suk
authors.initials: CS
authors.lastname: Chae
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Kwak
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Youngnim
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Yun Hyun
authors.initials: YH
authors.lastname: Huh
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Choong-Gu
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Yong-Wook
authors.initials: YW
authors.lastname: Park
authors.affiliation: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, and Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010641:Phenotype; D013583:Synovial Membrane / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse