| First Author | Ryu JH | Year | 2014 |
| Journal | PLoS Biol | Volume | 12 |
| Issue | 6 | Pages | e1001881 |
| PubMed ID | 24914685 | Mgi Jnum | J:213792 |
| Mgi Id | MGI:5586604 | Doi | 10.1371/journal.pbio.1001881 |
| Citation | Ryu JH, et al. (2014) Hypoxia-inducible factor-2alpha is an essential catabolic regulator of inflammatory rheumatoid arthritis. PLoS Biol 12(6):e1001881 |
| abstractText | 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-1alpha (encoded by HIF1A) and HIF-2alpha (encoded by EPAS1). HIF-2alpha was markedly up-regulated in the intimal lining of RA synovium, whereas HIF-1alpha was detected in a few cells in the sublining and deep layer of RA synovium. Overexpression of HIF-2alpha in joint tissues caused an RA-like phenotype, whereas HIF-1alpha did not affect joint architecture. Moreover, a HIF-2alpha deficiency in mice blunted the development of experimental RA. HIF-2alpha was expressed mainly in fibroblast-like synoviocytes (FLS) of RA synovium and regulated their proliferation, expression of RANKL (receptor activator of nuclear factor-kappaB ligand) and various catabolic factors, and osteoclastogenic potential. Moreover, HIF-2alpha-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-2alpha in joint tissues did not cause an RA phenotype. Thus, our results collectively suggest that HIF-2alpha plays a pivotal role in the pathogenesis of RA by regulating FLS functions, independent of HIF-1alpha. |
