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Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL\/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.<\/jats:p>","DOI":"10.3390\/ijms241310714","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:25:21Z","timestamp":1687911921000},"page":"10714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sirt6 Activation Ameliorates Inflammatory Bone Loss in Ligature-Induced Periodontitis in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Myung Jin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7720-3987","authenticated-orcid":false,"given":"Hyang Hwa","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Won","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Ryul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui-Sic","family":"Cho","sequence":"additional","affiliation":[{"name":"Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Kyeong","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5285-7618","authenticated-orcid":false,"given":"Young Jae","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea"},{"name":"Department of Orthopaedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref_1","unstructured":"CDC (2013, July 10). 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