Nature Medicine
11, 284 - 290 (2005)
Published online: 13 February 2005; | doi:10.1038/nm1194
Vav3 regulates osteoclast function and bone massRoberta Faccio1, 2, 3, Steven L Teitelbaum1, Keiko Fujikawa1, 5, Jean Chappel1, Alberta Zallone3, Victor L Tybulewicz4, F Patrick Ross1
& Wojciech Swat11
Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA. 2
Department of Orthopedic Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA. 3
University of Bari, School of Medicine, P. zza G. Cesare 11, Bari 70100, Italy. 4
Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. 5
Present address: Department of Biochemistry, Graduate School of Medicine, Hokkaido University, N15 W7, Sapporo 060-8638, Japan.
Correspondence should be addressed to F Patrick Ross rossf@wustl.edu or Wojciech Swat swat@pathbox.wustl.eduOsteoporosis, 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  v 3 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.
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