Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.

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)...

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Autores principales:	Je-Hwang Ryu, Chang-Suk Chae, Ji-Sun Kwak, Hwanhee Oh, Youngnim Shin, Yun Hyun Huh, Choong-Gu Lee, Yong-Wook Park, Churl-Hong Chun, Young-Myeong Kim, Sin-Hyeog Im, Jang-Soo Chun
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4e730e1e91e340d18d4720b3e8a542be
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spelling	oai:doaj.org-article:4e730e1e91e340d18d4720b3e8a542be2021-11-11T05:37:08ZHypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.1544-91731545-788510.1371/journal.pbio.1001881https://doaj.org/article/4e730e1e91e340d18d4720b3e8a542be2014-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24914685/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Rheumatoid 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.Je-Hwang RyuChang-Suk ChaeJi-Sun KwakHwanhee OhYoungnim ShinYun Hyun HuhChoong-Gu LeeYong-Wook ParkChurl-Hong ChunYoung-Myeong KimSin-Hyeog ImJang-Soo ChunPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 12, Iss 6, p e1001881 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Je-Hwang Ryu Chang-Suk Chae Ji-Sun Kwak Hwanhee Oh Youngnim Shin Yun Hyun Huh Choong-Gu Lee Yong-Wook Park Churl-Hong Chun Young-Myeong Kim Sin-Hyeog Im Jang-Soo Chun Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
description	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.
format	article
author	Je-Hwang Ryu Chang-Suk Chae Ji-Sun Kwak Hwanhee Oh Youngnim Shin Yun Hyun Huh Choong-Gu Lee Yong-Wook Park Churl-Hong Chun Young-Myeong Kim Sin-Hyeog Im Jang-Soo Chun
author_facet	Je-Hwang Ryu Chang-Suk Chae Ji-Sun Kwak Hwanhee Oh Youngnim Shin Yun Hyun Huh Choong-Gu Lee Yong-Wook Park Churl-Hong Chun Young-Myeong Kim Sin-Hyeog Im Jang-Soo Chun
author_sort	Je-Hwang Ryu
title	Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
title_short	Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
title_full	Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
title_fullStr	Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
title_full_unstemmed	Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
title_sort	hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4e730e1e91e340d18d4720b3e8a542be
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Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis.

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