Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial–mesenchymal transition in mice

Growing evidence suggests close associations between periodontitis and atherosclerosis.To further understand the pathological relationships of these associations,we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g.LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals.The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis,systemic inflammation,and atherosclerosis.Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas,but mice receiving ligature or ligature/P.g.LPS showed severe periodontitis,systemic inflammation,and aortic plaque formation.The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers.The severity of periodontitis was slightly higher in mice receiving ligature/P.g.LPS than ligature alone,and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g.LPS.These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis.In vitro,P.g.LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells.Moreover,secretory proteins,such as TNF-α,from macrophages induced endothelial–mesenchymal transitions of the endothelial cells.Taken together,systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via,in part,causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.

Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice

Bacterial infection is a common finding in patients,who develop medication-related osteonecrosis of the jaw(MRONJ)by the longterm and/or high-dose use of anti-resorptive agents such as bisphosphonate(BPs).However,pathological role of bacteria in MRONJ development at the early stage remains controversial.Here,we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model.C57/BL6 female mice were treated with intragastric broadspectrum antibiotics for 1 week.Zoledronic acid(ZOL)through intravenous injection and antibiotics in drinking water were administered for throughout the experiment.Pulp was exposed on the left maxillary first molar,then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal.All mice were harvested,and cecum,maxilla,and femurs were collected.ONJ development was assessed usingμCT and histologic analyses.When antibiotic was treated in mice,these mice had no weight changes,but developed significantly enlarged ceca compared to the control group(CTL mice).Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics,which was confirmed by decreased osteoclasts and inflammation.ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount.Furthermore,antibiotics treatment could further exacerbate bone necrosis,with increased osteoclast number.Our findings suggest that the commensal microbiome may play protective role,rather than pathological role,in the early stages of MRONJ development.