title: Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 "cherubism" mice.
abstract: While studies of the adaptor SH3BP2 have implicated a role in receptor-mediated signaling in mast cells and lymphocytes, they have failed to identify its function or explain why SH3BP2 missense mutations cause bone loss and inflammation in patients with cherubism. We demonstrate that Sh3bp2 "cherubism" mice exhibit trabecular bone loss, TNF-alpha-dependent systemic inflammation, and cortical bone erosion. The mutant phenotype is lymphocyte independent and can be transferred to mice carrying wild-type Sh3bp2 alleles through mutant fetal liver cells. Mutant myeloid cells show increased responses to M-CSF and RANKL stimulation, and, through mechanisms of increased ERK 1/2 and SYK phosphorylation/activation, they form macrophages that express high levels of TNF-alpha and osteoclasts that are unusually large. M-CSF and RANKL stimulation of myeloid cells that overexpress wild-type SH3BP2 results in similar large osteoclasts. This indicates that the mutant phenotype reflects gain of SH3BP2 function and suggests that SH3BP2 is a critical regulator of myeloid cell responses to M-CSF and RANKL stimulation.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ueki
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Makoto
authors.initials: M
authors.lastname: Senoo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ebihara
authors.forename: Naoki
authors.initials: N
authors.lastname: Agata
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onji
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saheki
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
authors.forename: Padma M
authors.initials: PM
authors.lastname: Mukherjee
authors.forename: Ernst
authors.initials: E
authors.lastname: Reichenberger
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology*; D039481:CD11b Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002636:Cherubism / Q000473:pathology*; D004195:Disease Models, Animal; D006402:Hematologic Diseases / Q000378:metabolism; D006720:Homozygote; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039481:CD11b Antigen; D047908:Intracellular Signaling Peptides and Proteins; D053245:RANK Ligand; C484644:Sh3bp2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D011392:Proline; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3