Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate

Danet, L.; Guiho, R.; Hussein, S.; Defois, A.; Gaigeard, N.; Veziers, J.; Mabilleau, G.; Hamel, A.; Waast, D.; Guicheux, J.; Boutet, M.-A.; Vinatier, C.

doi:10.1101/2025.10.28.684789

bioRxiv · 10.1101/2025.10.28.684789

Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate

Danet, L.·Guiho, R.·Hussein, S.·Defois, A.·Gaigeard, N.·Veziers, J.·Mabilleau, G.·Hamel, A.·Waast, D.·Guicheux, J.·Boutet, M.-A.·Vinatier, C.

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Abstract

BackgroundOsteoarthritis (OA) is the most common joint disease and is characterized by bone remodeling, cartilage degradation and synovial inflammation. To date, no effective treatment is available for this debilitating condition. Recent evidence suggests that mitochondrial dysfunction, including oxidative phosphorylation (OxPhos) failure, accumulates within OA chondrocytes and may contribute to pathogenesis. In this context, mitochondrial dysfunction may be associated with observable changes in mitochondrial number, size and shape. However, a comprehensive characterization of mitochondria-related features during OA, from tissue-to-cell level, is still lacking. Addressing these gaps could inform therapeutic strategies, such as the partial restoration of OxPhos, which has been proposed as a therapeutic approach. MethodsHere, we employed a multimodal approach that included Fourier-transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM) and real-time cellular metabolic assays (Seahorse technology) to better characterize mitochondrial parameters in cartilage during OA. Two types of experimental models were used using human cartilage: (1) undamaged versus damaged OA zones, and (2) non-OA versus OA samples. In addition, we investigated the potential of repurposing bezafibrate, an approved peroxisome proliferator-activated receptor (PPAR) agonist, as a mitochondria-based therapy to restore OxPhos in OA chondrocytes. ResultsWe identified that OA chondrocytes exhibit a decrease in glycogen deposits surface, and an increased number of mitochondria alongside an OxPhos dysfunction compared to non-OA chondrocytes. A similar trend toward glycogen storage deficiency and increased mitochondria number was observed in OA chondrocytes from damaged cartilage areas. Furthermore, multivariate analyses revealed that the clinical profiles of OA patients allowed OA chondrocytes to be separated into responders and non-responders to bezafibrate. ConclusionWe provide evidence that OA chondrocytes display decreased glycogen deposits surface, increased mitochondrial number and OxPhos dysfunction. Additionally, we identified that bezafibrate, a PPAR agonist, improved OxPhos function in a subgroup of OA chondrocytes derived from patients.

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Danet, L., Guiho, R., Hussein, S., Defois, A., Gaigeard, N., Veziers, J., Mabilleau, G., Hamel, A., Waast, D., Guicheux, J., Boutet, M.-A., Vinatier, C.. 2025-10-28. Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate. https://doi.org/10.1101/2025.10.28.684789

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