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Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration

BACKGROUND: Intervertebral disc (IVD) is a highly rhythmic tissue, which experiences a diurnal cycle of high/low mechanical loading via the changes of activity/rest phase. There are signs that disruption of the peripheral IVD clock is related to the process of intervertebral disc degeneration (IDD)....

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Autores principales: Peng, Pandi, Wang, Dong, Xu, Xiaolong, Wang, Di, Gao, Bo, Wang, Han, Jia, Haoruo, Shang, Qiliang, Zheng, Chao, Gao, Chu, Mao, Jianxin, Luo, Zhuojing, Yang, Liu, Hu, Xueyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347076/
https://www.ncbi.nlm.nih.gov/pubmed/35922862
http://dx.doi.org/10.1186/s13075-022-02876-w
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author Peng, Pandi
Wang, Dong
Xu, Xiaolong
Wang, Di
Gao, Bo
Wang, Han
Jia, Haoruo
Shang, Qiliang
Zheng, Chao
Gao, Chu
Mao, Jianxin
Luo, Zhuojing
Yang, Liu
Hu, Xueyu
author_facet Peng, Pandi
Wang, Dong
Xu, Xiaolong
Wang, Di
Gao, Bo
Wang, Han
Jia, Haoruo
Shang, Qiliang
Zheng, Chao
Gao, Chu
Mao, Jianxin
Luo, Zhuojing
Yang, Liu
Hu, Xueyu
author_sort Peng, Pandi
collection PubMed
description BACKGROUND: Intervertebral disc (IVD) is a highly rhythmic tissue, which experiences a diurnal cycle of high/low mechanical loading via the changes of activity/rest phase. There are signs that disruption of the peripheral IVD clock is related to the process of intervertebral disc degeneration (IDD). However, it is still unclear whether inflammation could disturb the IVD clock and thus induce the process of IDD. METHODS AND RESULTS: In this study, we used IL-1β, a commonly used inflammatory factor, to induce IDD and found that the IVD clock was dampened in degenerated human nucleus pulposus specimens, rat nucleus pulposus (NP) tissues, and cells. In this study, we found that the circadian clock of NP cells was totally disrupted by knockdown of the core clock gene brain and muscle arnt-like protein-1 (Bmal1), which thus induced the dysfunction of NP cells. Next, we explored the mechanism of dampened clock-induced IDD and found that knockdown of Bmal1 decreased the expression of nuclear factor erythroid2-related factor 2 (NRF2), a downstream target gene of Bmal1, and increased inflammatory response, oxidative stress reaction, and apoptosis of NP cells. In addition, NRF2 activation attenuated the dysfunction of NP cells induced by the dampened IVD clock and the degenerative process of NP tissues in an organotypic tissue-explant model. CONCLUSIONS: Taken together, our study extends the relationship between peripheral clock and IVD homeostasis and provides a potential therapeutic method for the prevention and recovery of IDD by targeting the clock-controlled gene Nrf2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02876-w.
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spelling pubmed-93470762022-08-04 Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration Peng, Pandi Wang, Dong Xu, Xiaolong Wang, Di Gao, Bo Wang, Han Jia, Haoruo Shang, Qiliang Zheng, Chao Gao, Chu Mao, Jianxin Luo, Zhuojing Yang, Liu Hu, Xueyu Arthritis Res Ther Research BACKGROUND: Intervertebral disc (IVD) is a highly rhythmic tissue, which experiences a diurnal cycle of high/low mechanical loading via the changes of activity/rest phase. There are signs that disruption of the peripheral IVD clock is related to the process of intervertebral disc degeneration (IDD). However, it is still unclear whether inflammation could disturb the IVD clock and thus induce the process of IDD. METHODS AND RESULTS: In this study, we used IL-1β, a commonly used inflammatory factor, to induce IDD and found that the IVD clock was dampened in degenerated human nucleus pulposus specimens, rat nucleus pulposus (NP) tissues, and cells. In this study, we found that the circadian clock of NP cells was totally disrupted by knockdown of the core clock gene brain and muscle arnt-like protein-1 (Bmal1), which thus induced the dysfunction of NP cells. Next, we explored the mechanism of dampened clock-induced IDD and found that knockdown of Bmal1 decreased the expression of nuclear factor erythroid2-related factor 2 (NRF2), a downstream target gene of Bmal1, and increased inflammatory response, oxidative stress reaction, and apoptosis of NP cells. In addition, NRF2 activation attenuated the dysfunction of NP cells induced by the dampened IVD clock and the degenerative process of NP tissues in an organotypic tissue-explant model. CONCLUSIONS: Taken together, our study extends the relationship between peripheral clock and IVD homeostasis and provides a potential therapeutic method for the prevention and recovery of IDD by targeting the clock-controlled gene Nrf2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02876-w. BioMed Central 2022-08-03 2022 /pmc/articles/PMC9347076/ /pubmed/35922862 http://dx.doi.org/10.1186/s13075-022-02876-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Peng, Pandi
Wang, Dong
Xu, Xiaolong
Wang, Di
Gao, Bo
Wang, Han
Jia, Haoruo
Shang, Qiliang
Zheng, Chao
Gao, Chu
Mao, Jianxin
Luo, Zhuojing
Yang, Liu
Hu, Xueyu
Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title_full Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title_fullStr Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title_full_unstemmed Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title_short Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration
title_sort targeting clock-controlled gene nrf2 ameliorates inflammation-induced intervertebral disc degeneration
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347076/
https://www.ncbi.nlm.nih.gov/pubmed/35922862
http://dx.doi.org/10.1186/s13075-022-02876-w
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