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

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

  • Br J Pharmacol. 2021 Aug;178(15):2931-2947. doi: 10.1111/bph.15466.
Gang Zhong 1 2 Huiping Long 2 Fei Chen 1 Yin Yu 1
Affiliations

Affiliations

  • 1 Center for Materials Synthetic Biology, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 2 Department of Neurology, Guangxi Medical University, Nanning, China.
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 CA2+ 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 CA2+ influx and activate Autophagy. Our results indicate that oxoglaucine has the potential to become a candidate drug for treatment of OA.

Keywords

TRPV5/CAMK-II/calmodulin pathway; autophagy; calcium channel; osteoarthritis; oxoglaucine.

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