Oxoglaucine mediates Ca²⁺ influx and activates autophagy to alleviate osteoarthritis through the TRPV5/calmodulin/CAMK‐II pathway

Abstract

Background and Purpose Stimulation of calcium influx and suppression of autophagy play important roles in the pathogenesis of osteoarthritis (OA). In this study, we used a novel inhibitor of TRPV5 cation channels ‐ oxoglaucine to attenuate progression of deterioration and pathological changes in OA patient‐derived chondrocytes and OA animal model, by activating autophagy. Experimental Approach Inhibition by oxoglaucine of calcium influx was assessed in cells.. Analyses were also carried out to investigate the effect of oxoglaucine on OA by detection of anti‐inflammatory response, TRPV5/CAMK‐II/calmodulin pathway, autophagy, and cartilage protection both in vitro and in vivo. demonstrated by macroscopic evaluation and histological findings. Key Results Oxoglaucine suppressed expression of proinflammatory and apoptosis‐related proteins, including TNF‐α, IL‐6, IL‐1β, MMP‐13, CASP‐3, and BAX, and prevented matrix degradation in OA chondrocytes. It also successfully blocked Ca 2+ influx, activating autophagy dose‐dependently asshown by up‐regulated expression of LC‐3II/I, Beclin‐1, ATG5, ATG7, higher autophagic influx and formation of autophagic vesicles. It also decreased expression of mRNA and protein of TRPV5, CAMK‐II, and calmodulin. Conversely, 1,25‐dihydroxyvitamin D3, anagonist of TRPV5 channels, reversed the oxoglaucine‐induced calcium influx inhibition and autophagy activation, demonstrating the association of oxoglaucine with TRPV5. Further, oxoglaucine prevented the apoptosis and matrix degradation of articular cartilage in a rat model of OA. Conclusion and Implications Oxoglaucine protects against cartilage damage by blocking the TRPV5/CAMK‐II/calmodulin pathway to inhibit Ca 2+ influx and activate autophagy. Our results indicate that oxoglaucine has the potential to become a candidate drug for treatment of OA.

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