Hypoxia-Inducible Factor-2 alpha 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-1 alpha (encoded by HIF1A) and HIF-2 alpha (encoded by EPAS1). HIF-2 alpha was markedly up-regulated in the intimal lining of RA synovium, whereas HIF-1 alpha was detected in a few cells in the sublining and deep layer of RA synovium. Overexpression of HIF-2 alpha in joint tissues caused an RA-like phenotype, whereas HIF-1 alpha did not affect joint architecture. Moreover, a HIF-2 alpha deficiency in mice blunted the development of experimental RA. HIF-2 alpha was expressed mainly in fibroblast-like synoviocytes (FLS) of RA synovium and regulated their proliferation, expression of RANKL (receptor activator of nuclear factor-kappa B ligand) and various catabolic factors, and osteoclastogenic potential. Moreover, HIF-2 alpha-dependent up-regulation of interleukin (IL)-6 in FLS stimulated differentiation of T(H)17 cells-crucial effectors of RA pathogenesis. Additionally, in the absence of IL-6 (Il6(-/-) mice), overexpression of HIF-2 alpha in joint tissues did not cause an RA phenotype. Thus, our results collectively suggest that HIF-2 alpha plays a pivotal role in the pathogenesis of RA by regulating FLS functions, independent of HIF-1 alpha.