Abstract

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.

Highlights

  • Introduction published maps and institutional affilRheumatoid arthritis (RA) impairs joint function because of joint destruction due to synovitis

  • We examined the effect of sustained hypoxia on Hypoxia inducible factor (HIF)-1α expression in MH7A cells in

  • We examined the effect of sustained hypoxia on HIF-1α expression in MH7A cells in response to hypoxia treatment

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Summary

Introduction

Introduction published maps and institutional affilRheumatoid arthritis (RA) impairs joint function because of joint destruction due to synovitis. The widespread use of biological agents against pro-inflammatory cytokines has enabled suppression of joint destruction, the effect is insufficient in certain cases [1]. The use of biological agents results in side effects, such as infections and allergies, as well as economic burden [2,3]; a different approach for treating RA is required [4]. RA-affected joint cavities are hypoxic due to inflammation [5]. Hypoxia inducible factor (HIF)-1α has been implicated in the cellular response to hypoxic stress. In case of a rapid change from normoxia to hypoxia, HIF-1α does not undergo PHD-mediated hydroxylation and is stable [7]. HIF-1α enhances the expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, via iations

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