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Previous studies have found that the traumatic occlusal force could aggravate alveolar bone loss during PD. However, the effect of reduced occlusal force during PD remains unclear. This study aimed to explore the effect of occlusal force unloading on PD onset and progression and its underlying mechanism as an effort to provide restoration suggestions for PD patients with dentition defect in clinic. This study might also propose occlusal force unloading could be a new local contributing factor for PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>C57BL\/6 mice were used to establish a PD model by the ligation of 5\u20130 silk around the mandibular left first molar (PD group) and an unloading experiment model by the extraction of their left maxillary first molar (EX group). The THP\u20101\u2010derived macrophages were used to verify <jats:italic>in vivo<\/jats:italic> results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Micro\u2010CT scanning and H&amp;E staining results consistently showed that PD\u2009+\u2009EX group experienced the most severe alveolar bone resorption as compared to PD group and control group. Further RNA\u2010sequencing analysis suggested that occlusal force unloading significantly enhanced osteoclastic resorption, inhibited osteoblastic activity, and promotes M1 and M2 macrophages polarization. Immunofluorescence staining (IF) results showed that compared with the PD group, PD\u2009+\u2009EX group significantly increased the ratio of M1\/M2 polarization. Similar results were observed by RT\u2010qPCR and IF <jats:italic>in vitro<\/jats:italic>: removal of compressive force led to an increased ratio of M1\/M2 polarization in LPS\u2010stimulated THP\u20101\u2010derived macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study demonstrated that occlusal force unloading aggravates bone resorption by increasing the ratio of M1\/M2 macrophages polarization during PD, suggesting a previously unknown local contributing factor for PD, and providing\u00a0a novel insight for dentists to restore missing teeth as an effort to maintain remaining dentition.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.13047","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T18:44:57Z","timestamp":1660675497000},"page":"1070-1082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Unloading of occlusal force aggravates alveolar bone loss in periodontitis"],"prefix":"10.1111","volume":"57","author":[{"given":"Rui","family":"Zhu","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyao","family":"Lu","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology Sichuan 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