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首页> 外文期刊>PLoS Biology >Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis
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Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis

机译：缺氧诱导因子2α是炎性类风湿关节炎的重要分解代谢调节剂

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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.
机译：类风湿关节炎（RA）是一种全身性自身免疫性疾病，表现为慢性炎症和关节组织破坏。但是，尚未完全阐明RA的病因和发病机理。在这里，我们探讨了缺氧诱导因子（HIFs），HIF-1α（由HIF1A编码）和HIF-2α（由EPAS1编码）的作用。 HIF-2α在RA滑膜的内膜中显着上调，而HIF-1α在RA滑膜的下层和深层的一些细胞中检测到。 HIF-2α在关节组织中的过表达引起RA样表型，而HIF-1α则不影响关节结构。此外，小鼠的HIF-2α缺乏抑制了实验性RA的发展。 HIF-2α主要在RA滑膜的成纤维样滑膜细胞（FLS）中表达，并调节其增殖，RANKL（核因子-κB受体激活剂）和各种分解代谢因子的表达以及破骨细胞的潜力。此外，FLS中HIF-2α依赖性白细胞介素（IL）-6的上调刺激了TH17细胞的分化，这是RA发病机理的重要影响因素。另外，在没有IL-6（Il6α/β小鼠）的情况下，在关节组织中HIF-2α的过表达不会引起RA表型。因此，我们的结果共同表明，HIF-2α通过调节FLS功能而独立于HIF-1α在RA的发病机制中起着关键作用。

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