title: Absence of Dap12 and the αvβ3 integrin causes severe osteopetrosis.
abstract: In vitro, ligand occupancy of αvβ3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only αvβ3, Dap12(-/-) mice exhibited a slight increase in bone mass, but Dap12(-/-) mice, lacking another ITAM protein, FcRγ, were severely osteopetrotic. The mechanism by which FcRγ compensates for Dap12 deficiency is unknown. We find that co-deletion of FcRγ did not exacerbate the skeletal phenotype of β3(-/-) mice. In contrast, β3/Dap12 double-deficient (DAP/β3(-/-)) mice (but not β1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking αvβ3 or Dap12 alone. Activation of OSCAR, the FcRγ co-receptor, rescued Dap12(-/-) but not DAP/β3(-/-)osteoclasts. Thus, the absence of αvβ3 precluded compensation for Dap12 deficiency by FcRγ. In keeping with this, Syk phosphorylation did not occur in OSCAR-activated DAP/β3(-/-) osteoclasts. Thus, FcRγ requires the osteoclast αvβ3 integrin to normalize the Dap12-deficient skeleton.
authors.affiliation: Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 teitelbs@wustl.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D020022:Genetic Predisposition to Disease; D039302:Integrin alphaVbeta3 / Q000172:deficiency* / Q000235:genetics; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D000072377:Syk Kinase; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; C450519:Oscar protein, mouse; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse