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.
Impaired clearance of amyloid-β peptide (Aβ) leads to abnormal extracellular accumulation of this neurotoxic protein that drives neurodegeneration in sporadic Alzheimer's disease (AD). Connective tissue growth factor (CTGF/CCN2) expression is elevated in plaque-surrounding astrocytes in AD patients. However, the role of CTGF in AD pathogenesis remains unclear. Here we characterized the neuroprotective activity of CTGF. We found that CTGF facilitated Aβ uptake and subsequent degradation within primary glia and neuroblastoma cells. CTGF enhanced extracellular Aβ degradation via membrane-bound matrix metalloproteinase-14 (MMP14) in glia and extracellular MMP13 in neurons. In the brain of a Drosophila AD model, glial-expression of CTGF reduced Aβ deposits, improved locomotor function, and rescued memory deficits. Neuroprotective potential of CTGF against Aβ42-induced photoreceptor degeneration was disrupted through silencing MMPs. Therefore, CTGF may represent a node for potential AD therapeutics as it intervenes in glia-neuron communication via specific MMPs to alleviate Aβ neurotoxicity in the central nervous system.
Apical periodontitis is a common infectious disease in human which primarily results from immune responses to bacterial challenge originated in the dental pulp (Nair, 1997). Host reactions are therefore major determinants for disease progression and prognosis of apical periodontitis. Exploration of factors governing the protective and destructive immunoreactions in the inflammatory environment of periapical lesions may shed light on new treatment strategy of the disease (Lin & Rosenberg, 2011).Resorption of periapical bone is a cardinal sign of apical periodontitis. Besides the increase of osteoclastic activity, attenuated osteoblastic function is also important for the development of inflammatory bone resorption (Marriott, 2013). Our previous
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