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The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress
Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) is an essential physiological metabolite from the mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-infla...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026041/ https://www.ncbi.nlm.nih.gov/pubmed/36924682 http://dx.doi.org/10.1016/j.redox.2023.102663 |
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author | Liu, Liang Zhang, Wanying Liu, Tanghao Tan, Yangfan Chen, Cheng Zhao, Jun Geng, Huan Ma, Chi |
author_facet | Liu, Liang Zhang, Wanying Liu, Tanghao Tan, Yangfan Chen, Cheng Zhao, Jun Geng, Huan Ma, Chi |
author_sort | Liu, Liang |
collection | PubMed |
description | Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) is an essential physiological metabolite from the mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-inflammation and antioxidation, and exhibits decreased serum levels with age. Herein, we aimed to investigate the effect and mechanism of α-KG on OA. We first quantified the α-KG levels in human cartilage tissue and osteoarthritic chondrocytes induced by IL-1β. Besides, IL-1β-induced osteoarthritic chondrocytes were treated with different concentrations of α-KG. Chondrocyte proliferation and apoptosis, synthesis and degradation of extracellular matrix, and inflammation mediators were analyzed. RNA sequencing was used to explore the mechanism of α-KG, and mitophagy and oxidative stress levels were further detected. These results were verified in an anterior cruciate ligament transection (ACLT) induced age-related OA rat model. We found that α-KG content decreased by 31.32% in damaged medial cartilage than in normal lateral cartilage and by 36.85% in IL-1β-induced human osteoarthritic chondrocytes compared to control. α-KG supplementation reversed IL-1β-induced chondrocyte proliferation inhibition and apoptosis, increased the transcriptomic and proteinic expression of ACAN and COL2A1 in vivo and in vitro, but inhibited the expression of MMP13, ADAMTS5, IL-6, and TNF-α. In mechanism, α-KG promoted mitophagy and inhibited ROS generation, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Overall, α-KG content decreased in human OA cartilage and IL-1β-induced osteoarthritic chondrocytes. Moreover, α-KG supplementation could alleviate osteoarthritic phenotype by regulating mitophagy and oxidative stress, suggesting its potential as a therapeutic target to ameliorate OA. |
format | Online Article Text |
id | pubmed-10026041 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-100260412023-03-21 The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress Liu, Liang Zhang, Wanying Liu, Tanghao Tan, Yangfan Chen, Cheng Zhao, Jun Geng, Huan Ma, Chi Redox Biol Research Paper Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) is an essential physiological metabolite from the mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-inflammation and antioxidation, and exhibits decreased serum levels with age. Herein, we aimed to investigate the effect and mechanism of α-KG on OA. We first quantified the α-KG levels in human cartilage tissue and osteoarthritic chondrocytes induced by IL-1β. Besides, IL-1β-induced osteoarthritic chondrocytes were treated with different concentrations of α-KG. Chondrocyte proliferation and apoptosis, synthesis and degradation of extracellular matrix, and inflammation mediators were analyzed. RNA sequencing was used to explore the mechanism of α-KG, and mitophagy and oxidative stress levels were further detected. These results were verified in an anterior cruciate ligament transection (ACLT) induced age-related OA rat model. We found that α-KG content decreased by 31.32% in damaged medial cartilage than in normal lateral cartilage and by 36.85% in IL-1β-induced human osteoarthritic chondrocytes compared to control. α-KG supplementation reversed IL-1β-induced chondrocyte proliferation inhibition and apoptosis, increased the transcriptomic and proteinic expression of ACAN and COL2A1 in vivo and in vitro, but inhibited the expression of MMP13, ADAMTS5, IL-6, and TNF-α. In mechanism, α-KG promoted mitophagy and inhibited ROS generation, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Overall, α-KG content decreased in human OA cartilage and IL-1β-induced osteoarthritic chondrocytes. Moreover, α-KG supplementation could alleviate osteoarthritic phenotype by regulating mitophagy and oxidative stress, suggesting its potential as a therapeutic target to ameliorate OA. Elsevier 2023-03-10 /pmc/articles/PMC10026041/ /pubmed/36924682 http://dx.doi.org/10.1016/j.redox.2023.102663 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Liu, Liang Zhang, Wanying Liu, Tanghao Tan, Yangfan Chen, Cheng Zhao, Jun Geng, Huan Ma, Chi The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title | The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title_full | The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title_fullStr | The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title_full_unstemmed | The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title_short | The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
title_sort | physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026041/ https://www.ncbi.nlm.nih.gov/pubmed/36924682 http://dx.doi.org/10.1016/j.redox.2023.102663 |
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