{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:16:53Z","timestamp":1791155813831,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T00:00:00Z","timestamp":1402358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-\u03b1 production and receptor activator of nuclear factor-\u03baB ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-\u03b1 is expressed in human cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-\u03b1 plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2KI\/KI). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-\u03b1\u2013mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-\u03b1\u2013mediated osteoclast formation and bone loss. Here, we show that bone marrow\u2013derived M-CSF\u2013dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2KI\/+) mice are highly responsive to TNF-\u03b1 and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase C\u03b32 (PLC\u03b32) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-\u03b1 injection model as well as in a human TNF-\u03b1 transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-\u03b1 expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-\u03b1\u2013induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2295","type":"journal-article","created":{"date-parts":[[2014,6,11]],"date-time":"2014-06-11T00:34:44Z","timestamp":1402446884000},"page":"2618-2635","source":"Crossref","is-referenced-by-count":61,"title":["SH3BP2 Cherubism Mutation Potentiates TNF-\u03b1\u2013Induced Osteoclastogenesis via NFATc1 and TNF-\u03b1\u2013Mediated Inflammatory Bone Loss"],"prefix":"10.1093","volume":"29","author":[{"given":"Tomoyuki","family":"Mukai","sequence":"first","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan"},{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remi","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and BiochemistryOkayama University Medical SchoolOkayamaJapan"},{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruhito","family":"Yoshitaka","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuho","family":"Kittaka","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan"},{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gallant","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ling","family":"Lin","sequence":"additional","affiliation":[{"name":"School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Rottapel","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of MedicineSaint Michael's HospitalTorontoCanada"},{"name":"Ontario Cancer Institute and the Campbell Family Cancer Research InstituteUniversity of TorontoTorontoCanada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Brotto","sequence":"additional","affiliation":[{"name":"School of Nursing & Health Studies and School of MedicineUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst J","family":"Reichenberger","sequence":"additional","affiliation":[{"name":"Department of Reconstructive Sciences, School of Dental MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Ueki","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri\u2013Kansas CityKansas CityMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,6,10]]},"reference":[{"issue":"11","key":"2024020318454427700_jbmr2295-bib-0001","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1136\/jcp.51.11.831","article-title":"Study of the cell biology and biochemistry of cherubism","volume":"51","author":"Southgate","year":"1998","journal-title":"J Clin Pathol."},{"issue":"1","key":"2024020318454427700_jbmr2295-bib-0002","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1086\/302456","article-title":"The gene for cherubism maps to chromosome 4p16","volume":"65","author":"Tiziani","year":"1999","journal-title":"Am J Hum 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