Abstract
Osteoporosis, a leading cause of morbidity in the elderly, is characterized by progressive loss of bone mass resulting from excess osteoclastic bone resorption relative to osteoblastic bone formation. Here we identify Vav3, a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo. Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading and resorptive activity resulting from impaired signaling downstream of the M-CSF receptor and alpha(v)beta3 integrin. Vav3-deficient mice have increased bone mass and are protected from bone loss induced by systemic bone resorption stimuli such as parathyroid hormone or RANKL. Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Density*
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Bone Resorption / physiopathology
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Carrier Proteins / pharmacology
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / physiology*
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Guanine Nucleotide Exchange Factors / physiology
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Integrin alphaVbeta3 / physiology
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Macrophage Colony-Stimulating Factor / pharmacology
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Membrane Glycoproteins / pharmacology
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Mice
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Osteoclasts / drug effects
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Osteoclasts / pathology
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Osteoclasts / physiology*
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-vav
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Rho Factor / physiology
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Carrier Proteins
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Cell Cycle Proteins
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Guanine Nucleotide Exchange Factors
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Integrin alphaVbeta3
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Rho Factor
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Vav3 protein, mouse
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Macrophage Colony-Stimulating Factor
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse