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, Tomoyuki Mukai Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Shu Ishida Department of Periodontal Medicine, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Remi Ishikawa Department of Molecular Biology and BiochemistryOkayama University Medical SchoolOkayamaJapan Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Teruhito Yosh*taka Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Mizuho Kittaka Department of Periodontal Medicine, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Richard Gallant Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Yi‐Ling Lin School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCAUSA Search for other works by this author on: Oxford Academic Robert Rottapel Division of Rheumatology, Department of MedicineSaint Michael's HospitalTorontoCanada Ontario Cancer Institute and the Campbell Family Cancer Research InstituteUniversity of TorontoTorontoCanada Search for other works by this author on: Oxford Academic Marco Brotto School of Nursing & Health Studies and School of MedicineUniversity of Missouri–Kansas CityKansas CityMOUSA Search for other works by this author on: Oxford Academic Ernst J Reichenberger Department of Reconstructive Sciences, School of Dental MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA Search for other works by this author on: Oxford Academic
Yasuyoshi Ueki Department of Oral and Craniofacial Sciences, School of DentistryUniversity of Missouri–Kansas CityKansas CityMOUSA Address correspondence to: Yasuyoshi Ueki, MD, PhD, Department of Oral and Craniofacial Sciences, University of Missouri–Kansas City, School of Dentistry, 650 E 25th Street, Kansas City, MO 64108, USA. E‐mail: uekiy@umkc.edu Search for other works by this author on: Oxford Academic
Journal of Bone and Mineral Research, Volume 29, Issue 12, 1 December 2014, Pages 2618–2635, https://doi.org/10.1002/jbmr.2295
Published:
10 June 2014
Article history
Received:
10 January 2014
Revision received:
19 May 2014
Accepted:
02 June 2014
Published:
10 June 2014
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Tomoyuki Mukai, Shu Ishida, Remi Ishikawa, Teruhito Yosh*taka, Mizuho Kittaka, Richard Gallant, Yi‐Ling Lin, Robert Rottapel, Marco Brotto, Ernst J Reichenberger, Yasuyoshi Ueki, SH3BP2 Cherubism Mutation Potentiates TNF‐α–Induced Osteoclastogenesis via NFATc1 and TNF‐α–Mediated Inflammatory Bone Loss, Journal of Bone and Mineral Research, Volume 29, Issue 12, 1 December 2014, Pages 2618–2635, https://doi.org/10.1002/jbmr.2295
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ABSTRACT
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)‐α production and receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation in myeloid cells. TNF‐α is expressed in human cherubism lesions, which contain a large number of tartrate‐resistant acid phosphatase (TRAP)‐positive multinucleated cells, and TNF‐α plays a critical role in inflammatory bone destruction in hom*ozygous cherubism mice (Sh3bp2KI/KI). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF‐α–mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF‐α–mediated osteoclast formation and bone loss. Here, we show that bone marrow–derived M‐CSF–dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2KI/+) mice are highly responsive to TNF‐α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF‐α injection model as well as in a human TNF‐α 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‐α expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF‐α–induced 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. © 2014 American Society for Bone and Mineral Research.
SH3BP2, CHERUBISM, TNF‐α, OSTEOCLAST, ARTHRITIS
© 2014 American Society for Bone and Mineral Research
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
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