title: SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss.
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 homozygous cherubism mice (Sh3bp2(KI/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 (Sh3bp2(KI/+) ) 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.
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mukai
authors.forename: Shu
authors.initials: S
authors.lastname: Ishida
authors.forename: Remi
authors.initials: R
authors.lastname: Ishikawa
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yoshitaka
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kittaka
authors.forename: Richard
authors.initials: R
authors.lastname: Gallant
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Marco
authors.initials: M
authors.lastname: Brotto
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Reichenberger
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ueki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002636:Cherubism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C484644:Sh3bp2 protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051966:Phospholipase C gamma
keywords: ARTHRITIS; CHERUBISM; OSTEOCLAST; SH3BP2; TNF-α