Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 3898
• Main Authors: Kaihara, Kenta, Nakagawa, Shuji, Arai, Yuji, Inoue, Hiroaki, Tsuchida, Shinji, Fujii, Yuta, Kamada, Yoichiro, Kishida, Tsunao, Mazda, Osam, Takahashi, Kenji
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.04.2021; MDPI
• Subjects: Angiogenesis; Arthritis; Cartilage; Collagen; Cytokines; Deferoxamine; Destruction; Feedback; HIF-1 alpha; Hypoxia; Hypoxia-inducible factor 1a; Immunization; Inflammation; Joints (anatomy); Negative feedback; Pathogenesis; Proteins; Rheumatoid arthritis; Risk groups; Transcription; Tumor necrosis factor-TNF; hypoxia; rheumatoid arthritis; HIF-1 alpha
• DOI: 10.3390/ijms22083898
• ISSN: 1422-0067; 1661-6596

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 ( < 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 ( < 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.