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However, the role of osteocytes in LIP remains unclear. Furthermore, there is no consensus on the choice of alveolar bone parameters and time points to evaluate LIP. Here, we investigated the dynamics of changes in osteoclastogenesis and bone volume (BV) loss in LIP over 14\u2009days. Time-course analysis revealed that osteoclast induction peaked on days 3 and 5, followed by the peak of BV loss on day 7. Notably, BV was restored by day 14. The bone formation phase after the bone resorption phase was suggested to be responsible for the recovery of bone loss. Electron microscopy identified bacteria in the osteocyte lacunar space beyond the periodontal ligament (PDL) tissue. We investigated how osteocytes affect bone resorption of LIP and found that mice lacking receptor activator of NF-\u03baB ligand (RANKL), predominantly in osteocytes, protected against bone loss in LIP, whereas recombination activating 1 (RAG1)-deficient mice failed to resist it. These results indicate that T\/B cells are dispensable for osteoclast induction in LIP and that RANKL from osteocytes and mature osteoblasts regulates bone resorption by LIP. Remarkably, mice lacking the myeloid differentiation primary response gene 88 (MYD88) did not show protection against LIP-induced bone loss. Instead, osteocytic cells expressed nucleotide-binding oligomerization domain containing 1 (NOD1), and primary osteocytes induced significantly higher Rankl than primary osteoblasts when stimulated with a NOD1 agonist. Taken together, LIP induced both bone resorption and bone formation in a stage-dependent manner, suggesting that the selection of time points is critical for quantifying bone loss in mouse LIP. Pathogenetically, the current study suggests that bacterial activation of osteocytes via NOD1 is involved in the mechanism of osteoclastogenesis in LIP. The NOD1-RANKL axis in osteocytes may be a therapeutic target for bone resorption in periodontitis. \u00a9 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4897","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T07:45:41Z","timestamp":1691480741000},"page":"1521-1540","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Osteocyte RANKL Drives Bone Resorption in Mouse Ligature-Induced Periodontitis"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3626-1638","authenticated-orcid":false,"given":"Mizuho","family":"Kittaka","sequence":"first","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus E","family":"Levitan","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0792-2847","authenticated-orcid":false,"given":"Rina","family":"Urata","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy B","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine Indianapolis IN USA"},{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayoi","family":"Teno","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixia","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences University of Missouri Kansas City, School of Dentistry Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Kitase","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine Indianapolis IN USA"},{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9211-9698","authenticated-orcid":false,"given":"Matthew","family":"Prideaux","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine Indianapolis IN USA"},{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5197-891X","authenticated-orcid":false,"given":"Sarah L","family":"Dallas","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences University of Missouri Kansas City, School of Dentistry Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3989-4780","authenticated-orcid":false,"given":"Alexander G","family":"Robling","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine Indianapolis IN USA"},{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8660-626X","authenticated-orcid":false,"given":"Yasuyoshi","family":"Ueki","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,1]]},"reference":[{"issue":"5","key":"2024053104014993400_jbmr4897-bib-0001","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1902\/jop.2015.140520","article-title":"Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012","volume":"86","author":"Eke","year":"2015","journal-title":"J 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