Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α
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 fibroblas...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/8/3898 |
| _version_ | 1797538219327225856 |
|---|---|
| author | Kenta Kaihara Shuji Nakagawa Yuji Arai Hiroaki Inoue Shinji Tsuchida Yuta Fujii Yoichiro Kamada Tsunao Kishida Osam Mazda Kenji Takahashi |
| author_facet | Kenta Kaihara Shuji Nakagawa Yuji Arai Hiroaki Inoue Shinji Tsuchida Yuta Fujii Yoichiro Kamada Tsunao Kishida Osam Mazda Kenji Takahashi |
| author_sort | Kenta Kaihara |
| collection | DOAJ |
| description | 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 (<i>p</i> < 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 (<i>p</i> < 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. |
| first_indexed | 2024-03-10T12:27:26Z |
| format | Article |
| id | doaj.art-d3568ef6f9194b9787245b59122031e4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:27:26Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d3568ef6f9194b9787245b59122031e42023-11-21T14:55:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228389810.3390/ijms22083898Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1αKenta Kaihara0Shuji Nakagawa1Yuji Arai2Hiroaki Inoue3Shinji Tsuchida4Yuta Fujii5Yoichiro Kamada6Tsunao Kishida7Osam Mazda8Kenji Takahashi9Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Sports and Para-Sports Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Sports and Para-Sports Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanHypoxia 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 (<i>p</i> < 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 (<i>p</i> < 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.https://www.mdpi.com/1422-0067/22/8/3898rheumatoid arthritishypoxiaHIF-1 alpha |
| spellingShingle | Kenta Kaihara Shuji Nakagawa Yuji Arai Hiroaki Inoue Shinji Tsuchida Yuta Fujii Yoichiro Kamada Tsunao Kishida Osam Mazda Kenji Takahashi Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α International Journal of Molecular Sciences rheumatoid arthritis hypoxia HIF-1 alpha |
| title | Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α |
| title_full | Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α |
| title_fullStr | Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α |
| title_full_unstemmed | Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α |
| title_short | Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α |
| title_sort | sustained hypoxia suppresses joint destruction in a rat model of rheumatoid arthritis via negative feedback of hypoxia inducible factor 1α |
| topic | rheumatoid arthritis hypoxia HIF-1 alpha |
| url | https://www.mdpi.com/1422-0067/22/8/3898 |
| work_keys_str_mv | AT kentakaihara sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT shujinakagawa sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT yujiarai sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT hiroakiinoue sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT shinjitsuchida sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT yutafujii sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT yoichirokamada sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT tsunaokishida sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT osammazda sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a AT kenjitakahashi sustainedhypoxiasuppressesjointdestructioninaratmodelofrheumatoidarthritisvianegativefeedbackofhypoxiainduciblefactor1a |