{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:05:59Z","timestamp":1789416359581,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE027070"],"award-info":[{"award-number":["DE027070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and objective<\/jats:title><jats:p>Clinical studies have shown that metabolic syndrome (MetS) exacerbates periodontitis. However, the underlying mechanisms remain largely unknown. Since our animal study has shown that high\u2010fat diet\u2010induced MetS exacerbates lipopolysaccharide (LPS)\u2010stimulated periodontitis in mouse model and our in vitro study showed that acid sphingomyelinase (aSMase) plays a key role in the amplification of LPS\u2010triggered pro\u2010inflammatory response by palmitic acid (PA) in macrophages, we tested our hypothesis that inhibitor of aSMase attenuates MetS\u2010exacerbated periodontitis in animal model. Furthermore, to explore the potential underlying mechanisms, we tested our hypothesis that aSMase inhibitor downregulates pro\u2010inflammatory and pro\u2010osteoclastogenic gene expression in macrophages in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and methods<\/jats:title><jats:p>We induced MetS and periodontitis in C57BL\/6\u00a0mice by feeding high\u2010fat diet (HFD) and periodontal injection of A.\u00a0<jats:italic>actinomycetemcomitans<\/jats:italic> LPS, respectively, and treated mice with imipramine, a well\u2010established inhibitor of aSMase. Micro\u2010computed tomography (micro\u2010CT), tartrate\u2010resistant 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\u2010inflammatory gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis 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\u2010exacerbated periodontitis, we showed that imipramine inhibited the upregulation of pro\u2010inflammatory cytokines and transcription factor c\u2010FOS as well as ceramide production by LPS plus PA in macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This 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\u2010inflammatory and pro\u2010osteoclastogenic gene expression in macrophages in vitro. This study provides the first evidence that aSMase is a potential therapeutic target for MetS\u2010exacerbated periodontitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12951","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:07:24Z","timestamp":1636394844000},"page":"173-185","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Inhibition of acid sphingomyelinase by imipramine abolishes the synergy between metabolic syndrome and periodontitis on alveolar bone loss"],"prefix":"10.1111","volume":"57","author":[{"given":"Yanchun","family":"Li","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Medical Genetics Department of Medicine College of Medicine Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyang","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Medical Genetics Department of Medicine College of Medicine Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral Biology School of Dental Medicine University at Buffalo  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron L.","family":"Kirkwood","sequence":"additional","affiliation":[{"name":"Department of Oral Biology School of Dental Medicine University at Buffalo  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4519-8973","authenticated-orcid":false,"given":"Keith L.","family":"Kirkwood","sequence":"additional","affiliation":[{"name":"Department of Oral Biology School of Dental Medicine University at Buffalo  New York New York USA"},{"name":"Department of Head and Neck\/Plastic and Reconstructive Surgery Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Lopes\u2010Virella","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Medical Genetics Department of Medicine College of Medicine Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Ralph H. 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