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 tricarboxylic
acid (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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: November 18, 2022
Accepted:
November 12,
2022
Received:
May 27,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
