C-N Yang1, S-H Kok1,2, H-W Wang2, J Z-C Chang1,2, E H-H Lai1,2, C-T Shun3, H Yang2, M-H Chen2, C-Y Hong1,2,4,5, S-K Lin1,2. 1. Department of Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan. 2. Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. 3. Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan. 4. Department of Prosthodontics, School of Dentistry, China Medical University, Taichung, Taiwan. 5. College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan.
Abstract
AIM: To assess the connection between mitophagy and hypoxia-induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of mitophagy-related apoptosis. METHODOLOGY: Hypoxia-induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated, respectively, by MitoSOX and JC-1 fluorescence dye signalling. Accumulation of mitophagy markers PTEN-induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved-poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. anova, Fisher's and Student's t-test were used for data analysis. RESULTS: Hypoxia-induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia-augmented apoptotic activity. Simvastatin alleviated hypoxia-induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its antimitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts. CONCLUSIONS: The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.
AIM: To assess the connection between mitophagy and hypoxia-induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of mitophagy-related apoptosis. METHODOLOGY:Hypoxia-induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated, respectively, by MitoSOX and JC-1 fluorescence dye signalling. Accumulation of mitophagy markers PTEN-induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved-poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. anova, Fisher's and Student's t-test were used for data analysis. RESULTS:Hypoxia-induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia-augmented apoptotic activity. Simvastatin alleviated hypoxia-induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its antimitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts. CONCLUSIONS: The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.