Inhibition of acid sphingomyelinase by imipramine abolishes the synergy between metabolic syndrome and periodontitis on alveolar bone loss.

BACKGROUND AND

objectiveClinical studies have shown that metabolic syndrome (MetS) exacerbates periodontitis. However, the underlying mechanisms remain largely unknown. Since our animal study has shown that high-fat diet-induced MetS exacerbates lipopolysaccharide (LPS)-stimulated periodontitis in mouse model and our in vitro study showed that acid sphingomyelinase (aSMase) plays a key role in the amplification of LPS-triggered pro-inflammatory response by palmitic acid (PA) in macrophages, we tested our hypothesis that inhibitor of aSMase attenuates MetS-exacerbated periodontitis in animal model. Furthermore, to explore the potential underlying mechanisms, we tested our hypothesis that aSMase inhibitor downregulates pro-inflammatory and pro-osteoclastogenic gene expression in macrophages in vitro. MATERIAL AND

methodsWe induced MetS and periodontitis in C57BL/6 mice by feeding high-fat diet (HFD) and periodontal injection of A. actinomycetemcomitans LPS, respectively, and treated mice with imipramine, a well-established inhibitor of aSMase. Micro-computed tomography (micro-CT), tartrate-resistant acid phosphatase staining, histological and pathological evaluations as well as cell cultures were performed to evaluate alveolar bone loss, osteoclast formation, periodontal inflammation and pro-inflammatory gene expression.

resultsAnalysis of metabolic parameter showed that while HFD induced MetS by increasing bodyweight, insulin resistance, cholesterol and free fatty acids, imipramine reduced free fatty acids but had no significant effects on other metabolic parameters. MicroCT showed that either MetS or periodontitis significantly reduced bone volume fraction (BVF) of maxilla and the combination of MetS and periodontitis further reduced BVF. However, imipramine increased BVF in mice with both MetS and periodontitis to a level similar to that in mice with periodontitis alone, suggesting that imipramine abolished the synergy between MetS and periodontitis on alveolar bone loss. Consistently, results showed that imipramine inhibited osteoclast formation and periodontal inflammation in mice with both MetS and periodontitis. To elucidate the mechanisms by which imipramine attenuates MetS-exacerbated periodontitis, we showed that imipramine inhibited the upregulation of pro-inflammatory cytokines and transcription factor c-FOS as well as ceramide production by LPS plus PA in macrophages.

conclusionThis study has shown that imipramine as an inhibitor of aSMase abolishes the synergy between MetS and periodontitis on alveolar bone loss in animal model and inhibits pro-inflammatory and pro-osteoclastogenic gene expression in macrophages in vitro. This study provides the first evidence that aSMase is a potential therapeutic target for MetS-exacerbated periodontitis.