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However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-\u03b1 and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-\u03b1 and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption.<\/jats:p>","DOI":"10.3390\/ijms23105630","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T03:20:43Z","timestamp":1652844043000},"page":"5630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Locally Secreted Semaphorin 4D Is Engaged in Both Pathogenic Bone Resorption and Retarded Bone Regeneration in a Ligature-Induced Mouse Model of Periodontitis"],"prefix":"10.3390","volume":"23","author":[{"given":"Takenobu","family":"Ishii","sequence":"first","affiliation":[{"name":"Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Ruiz-Torruella","sequence":"additional","affiliation":[{"name":"Institute Sant Joan, Carrer de Sant Joan, 26, Rub\u00ed, 08191 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-8603","authenticated-orcid":false,"given":"Kenta","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuguno","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Research and Development, LION Corporation, Odawara 256-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Heidari","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roodelyne","family":"Pierrelus","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Leon","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Rawas-Qalaji","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Pastore","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Periodontics and Endodontics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-1523","authenticated-orcid":false,"given":"Hani","family":"Mawardi","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences, Faculty of Dentistry, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umadevi","family":"Kandalam","sequence":"additional","affiliation":[{"name":"Woody L. Hunt School of Dental Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Hardigan","sequence":"additional","affiliation":[{"name":"Patel College of Allopathic Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1458-6527","authenticated-orcid":false,"given":"Lukasz","family":"Witek","sequence":"additional","affiliation":[{"name":"Division of Biomaterials, NYU College of Dentistry, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo G.","family":"Coelho","sequence":"additional","affiliation":[{"name":"Division of Biomaterials, NYU College of Dentistry, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihisa","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Davie, Fort Lauderdale, FL 33328, USA"},{"name":"Cell Therapy Institute, Center for Collaborative Research, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/prd.12323","article-title":"Recent epidemiologic trends in periodontitis in the USA","volume":"82","author":"Eke","year":"2019","journal-title":"Periodontol. 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s10266-006-0060-6","article-title":"Periodontal disease and systemic conditions: A bidirectional relationship","volume":"94","author":"Kim","year":"2006","journal-title":"Odontology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bj.2018.12.001","article-title":"Association between periodontal pathogens and systemic disease","volume":"42","author":"Bui","year":"2019","journal-title":"Biomed. 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