Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Liang, Zhang, Wanying, Liu, Tanghao, Tan, Yangfan, Chen, Cheng, Zhao, Jun, Geng, Huan, Ma, Chi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
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
_version_ 1784909461467430912
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
work_keys_str_mv AT liuliang thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT zhangwanying thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT liutanghao thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT tanyangfan thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT chencheng thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT zhaojun thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT genghuan thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT machi thephysiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT liuliang physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT zhangwanying physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT liutanghao physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT tanyangfan physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT chencheng physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT zhaojun physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT genghuan physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress
AT machi physiologicalmetaboliteaketoglutarateamelioratesosteoarthritisbyregulatingmitophagyandoxidativestress