Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

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.

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

“…Here, it should be emphasized that apoptosis of osteoblasts was also shown to be directly induced under some pathological agents, such as hypoxia 164 , Es deficiency 165 , aging 166 , and GCs 167 , etc, which enhanced the reduction of the number of osteocyte processes, eventually leading to increased bone resorption and decreased BMD. However, autophagy or apoptosis of osteocytes, as the most abundant cells in bone, could have a more important role in osteoclastogenesis-triggered bone loss, compared with apoptosis of osteoblasts.…”

The Role of Autophagy and Mitophagy in Bone Metabolic Disorders

“…However, Li et al [115] found that nano-sized Al2O3 particle induced autophagy in fibroblasts which reduced RANKL expression and negatively regulated the differentiation and maturation of osteoclasts, hence alleviated osteolysis. Furthermore, a few investigations of autophagy involvement in osteolysis in animal models indicated that the inhibition of autophagy decreased osteolysis severity [19,24,50,51,115]. Therefore, inducing autophagy in fibroblasts to limit the activation of RANKL on osteoclasts may be a potential therapeutic target for the prevention and treatment of osteolysis.…”

“…Yang et al 49 used dexamethasone to treat rats with induced osteoporosis, and found that resveratrol further promoted SIRT1 (Sirtuin1)-induced mitophagy activation by suppressing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. In addition, in inflammation-associated bone loss, such as bone resorption in apical periodontitis, simvastatin inhibited mitophagy and apoptosis of regional osteoblasts to modulate the balance between tissue destruction and regeneration 50 .…”

Autophagy and its significance in periodontal disease

“…A recent study found that autophagy induced by rough surfaces of dental implants accelerated the transition from osteoblast proliferation to maturation and the subsequent differentiation into osteocytes 111 . Moreover, anti‐inflammatory action enhanced autophagy and suppressed apoptosis of osteoblasts, suggesting that autophagy of osteoblasts alleviates bone loss associated with inflammation 112,113 …”

“…111 Moreover, anti-inflammatory action enhanced autophagy and suppressed apoptosis of osteoblasts, suggesting that autophagy of osteoblasts alleviates bone loss associated with inflammation. 112,113 Osteoblast differentiation is accompanied by changes in cell morphology and intracellular organelle contents. Terminally, osteoblasts transform into osteocytes and localize to mineralized bone matrix.…”