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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,28]]},"abstract":"<jats:p>Excess bone loss due to increased osteoclastogenesis is a significant clinical problem. Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation. The role of IFT80, an IFT complex B protein, in osteoclasts (OCs) is completely unknown. Here, we demonstrate that deletion of IFT80 in the myeloid lineage led to increased OC formation and activity accompanied by severe bone loss in mice. IFT80 regulated OC formation by associating with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) to promote protein stabilization and proteasomal degradation of tumor necrosis factor (TNF) receptor\u2013associated factor 6 (TRAF6). IFT80 knockdown resulted in increased ubiquitination of Cbl-b and higher TRAF6 levels, thereby hyperactivating the receptor activator of nuclear factor-\u03ba\u03b2 (NF-\u03ba\u03b2) ligand (RANKL) signaling axis and increased OC formation. Ectopic overexpression of IFT80 rescued osteolysis in a calvarial model of bone loss. We have thus identified a negative function of IFT80 in OCs.<\/jats:p>","DOI":"10.1073\/pnas.2201490119","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:48Z","timestamp":1655942448000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":32,"title":["IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation"],"prefix":"10.1073","volume":"119","author":[{"given":"Vishwa","family":"Deepak","sequence":"first","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY 14214"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9380-2712","authenticated-orcid":false,"given":"Ding","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY 14214"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merry Jo","family":"Oursler","sequence":"additional","affiliation":[{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905"},{"name":"Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-6901","authenticated-orcid":false,"given":"Shuying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Center for Innovation &amp; 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