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Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis

  • Xiaoxin Wu
    Affiliations
    Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

    Department of Orthopaedic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
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  • Chamikara Liyanage
    Affiliations
    Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

    Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia
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  • Manuel Plan
    Affiliations
    Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia

    Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
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  • Terra Stark
    Affiliations
    Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia

    Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
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  • Tim McCubbin
    Affiliations
    Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia

    Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
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  • Roberto A. Barrero
    Affiliations
    eResearch Office, Queensland University of Technology, Brisbane, QLD 4000, Australia
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  • Jyotsna Batra
    Affiliations
    Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

    Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia
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  • Ross Crawford
    Affiliations
    The Prince Charles Hospital, Chermside, Brisbane, QLD 4032, Australia
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  • Yin Xiao
    Affiliations
    Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

    Australia–China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, QLD 4059, Australia
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  • Author Footnotes
    1 W: www.qut.edu.au/ihbi.
    ,
    Author Footnotes
    2 Twitter: @drprasadam.
    Indira Prasadam
    Correspondence
    Corresponding author. NHMRC Emerging Leadership Fellow Stem cell and Tissue Engineering Program Biomimetic Technologies for Cartilage repair and Arthritis (BT-CRA) SEF Faculty Research Ethics, and Integrity Advisor Centre for Biomedical Technologies |School of Mechanical, Medical and Process Engineering |Queensland University of Technology 60 Musk Ave/cnr. Blamey St, Kelvin Grove, QLD, 4059, Australia T: +617 3138 6137 | M: +61 0469 117 898 | F: +617 3138 6030
    Footnotes
    1 W: www.qut.edu.au/ihbi.
    2 Twitter: @drprasadam.
    Affiliations
    Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia
    Search for articles by this author
  • Author Footnotes
    1 W: www.qut.edu.au/ihbi.
    2 Twitter: @drprasadam.
Published:November 18, 2022DOI:https://doi.org/10.1016/j.joca.2022.11.004

      Summary

      Objectives

      Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage.

      Methods

      Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes.

      Results

      OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the TCA cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions.

      Conclusion

      This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.

      Graphical abstract

      Keywords

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