Cuproptosis in osteoarthritis: Exploring chondrocyte cuproptosis and therapeutic avenues

Background

Cuproptosis, a newly identified form of cell death, presents an as-yet-unclear potential correlation with Osteoarthritis (OA) pathogenesis. This study aimed to explore the relationship between chondrocyte cuproptosis and OA, and to evaluate the therapeutic potential of the copper ion chelator tetrathiomolybdate (TTM) in OA treatment.

Methods

We collected clinical cartilage samples and animal specimens, employing Micro-CT, histopathological staining, immunohistochemistry, and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) to evaluate the potential occurrence of chondrocyte cuproptosis during OA progression. In vitro, we used elesclomol and copper sulfate to create a cuproptosis model in mouse chondrocytes. Techniques like ICP-MS, CCK-8, and others were used to explore the role of cuproptosis in OA development. To assess if TTM can mitigate chondrocyte cuproptosis and decelerate OA progression, various methods were applied at cellular and animal levels. Metabolomics predicted pathways for TTM's potential OA improvement. Molecular docking was employed to predict the intervention target of TTM. The impact of glutathione (GSH) on chondrocyte cuproptosis and OA development was studied using si-glutathione synthetase (si-GSS) plasmid knockdown and exogenous GSH supplements.

Results

Our findings indicate that in the process of OA, chondrocytes show an increase in copper ion content, metabolic disorders of the cartilage matrix, low expression of cuproptosis - related proteins lipoamide dehydrogenase (DLAT), dihydrolipoamide succinyltransferase (DLST), and ferredoxin 1 (FDX1), and high expression of the heat shock protein70 (HSP70). As the primary target of cuproptosis, mitochondria experience significant impacts on respiratory function and morphology during this process. TTM enhances chondrocytes resistance to cuproptosis by promoting GSH expression, thus ameliorating the OA phenotype.

Conclusion

Chondrocyte cuproptosis is integral to pathogenesis and progression of OA, and TTM has emerged as a novel and potentially valuable therapeutic strategy for the treatment of this disease.

The translational potential of this article

Chondrocyte cuproptosis plays a key role in the occurrence and development of knee osteoarthritis. The copper ion chelator (Tetrathiomolybdate) has been proved to be able to treat knee osteoarthritis by alleviating chondrocyte cuproptosis.