2. Academic Validation
  3. The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

  • Redox Biol. 2023 Mar 10;62:102663. doi: 10.1016/j.redox.2023.102663.
Liang Liu 1,  Wanying Zhang 2,  Tanghao Liu 3,  Yangfan Tan 3,  Cheng Chen 4,  Jun Zhao 5,  Huan Geng 6,  Chi Ma 7
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 2 Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 3 Department of Orthopedics, The First Affiliated Hospital of Jishou University, Jishou, 416000, China.
  • 4 Department of Orthopedics, The Affiliated 926 Hospital of Kunming University of Science and Technology, Kaiyuan, China.
  • 5 Department of Orthopedics, The First Affiliated Hospital of Jishou University, Jishou, 416000, China. Electronic address: [email protected].
  • 6 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address: [email protected].
  • 7 Department of Orthopedics, The First Affiliated Hospital of Jishou University, Jishou, 416000, China; Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
PMID: 36924682 DOI: 10.1016/j.redox.2023.102663
Abstract

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.

Keywords

Cartilage; Mitophagy; Osteoarthritis; Oxidative stress; α-ketoglutarate.

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