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Vav3 regulates osteoclast function and bone mass

Nature Medicine volume 11, pages 284–290 (2005)Cite this article

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 αvβ3 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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Figure 1: Vav3−/− and Vav1−/−Vav3−/− mice develop osteosclerosis.
Figure 2: Vav3−/− mice are protected from PTH- or RANKL-induced bone loss.
Figure 3: RANKL and M-CSF signaling is unaltered in Vav3−/− and Vav1−/−Vav3−/− osteoclastic cells.
Figure 4: Morphological and functional defects of Vav3−/− and Vav1−/−Vav3−/− osteoclasts.
Figure 5: Re-expression of Vav3, but not Vav1, rescues in vitro differentiation of Vav3−/− osteoclasts.
Figure 6: Defective M-CSF- and αvβ3-dependent signaling and Rac activation in Vav3−/− and Vav1−/−Vav3−/− osteoclasts.

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References

  1. Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Bustelo, X.R. Vav proteins, adaptors and cell signaling. Oncogene 20, 6372–6381 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Turner, M. & Billadeau, D.D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat. Rev. Immunol. 2, 476–486 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Holsinger, L.J. et al. Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr. Biol. 8, 563–572 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Fischer, K.D. et al. Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr. Biol. 8, 554–562 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Cella, M. et al. Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity. J. Exp. Med. 200, 817–823 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Manetz, T.S. et al. Vav1 regulates phospholipase C{gamma} activation and calcium responses in mast cells. Mol. Cell. Biol. 21, 3763–3774 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Doody, G.M. et al. Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Nat. Immunol. 2, 542–547 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Gotoh, A., Takahira, H., Geahlen, R.L. & Broxmeyer, H.E. Cross-linking of integrins induces tyrosine phosphorylation of the proto-oncogene product Vav and the protein tyrosine kinase Syk in human factor-dependent myeloid cells. Cell Growth Differ. 8, 721–729 (1997).

    CAS  PubMed  Google Scholar 

  10. Zheng, L., Sjolander, A., Eckerdal, J. & Andersson, T. Antibody-induced engagement of beta 2 integrins on adherent human neutrophils triggers activation of p21ras through tyrosine phosphorylation of the protooncogene product Vav. Proc. Natl. Acad. Sci. USA 93, 8431–8436 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yron, I. et al. Integrin-dependent tyrosine phosphorylation and growth regulation by Vav. Cell Adhes. Commun. 7, 1–11 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Riteau, B., Barber, D.F. & Long, E.O. Vav1 phosphorylation is induced by β2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J. Exp. Med. 198, 469–474 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cichowski, K., Brugge, J.S. & Brass, L.F. Thrombin receptor activation and integrin engagement stimulate tyrosine phosphorylation of the proto-oncogene product, p95vav, in platelets. J. Biol. Chem. 271, 7544–7550 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. del Pozo, M.A. et al. Guanine exchange-dependent and -independent effects of Vav1 on integrin-induced T cell spreading J. Immunol. 170, 41–47 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Marignani, P.A. & Carpenter, C.L. Vav2 is required for cell spreading. J. Cell Biol. 154, 177–186 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miranti, C.K., Leng, L., Maschberger, P., Brugge, J.S. & Shattil, S.J. Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1. Curr. Biol. 8, 1289–1299 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Obergfell, A. et al. Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton. J. Cell Biol. 157, 265–275 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Moores, S.L. et al. Vav family proteins couple to diverse cell surface receptors. Mol. Cell. Biol. 20, 6364–6373 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gakidis, M.A.M. et al. Vav GEFs are required for β2 integrin-dependent functions of neutrophils. J. Cell Biol. 166, 273–282 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Zambonin-Zallone, A. et al. Immunocytochemical distribution of extracellular matrix receptors in human osteoclasts: A β3 integrin is colocalized with vinculin and talin in the podosomes of osteoclastoma giant cells. Exp. Cell Res. 182, 645–652 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Lakkakorpi, P.T. & Vaananen, H.K. Kinetics of the osteoclast cytoskeleton during the resorption cycle in vitro. J. Bone Miner. Res. 6, 817–826 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Vaananen, H.K., Zhao, H., Mulari, M. & Halleen, J.M. The cell biology of osteoclast function. J.Cell Sci. 113, 377–381 (2000).

    CAS  PubMed  Google Scholar 

  24. Destaing, O., Saltel, F., Geminard, J.-C., Jurdic, P. & Bard, F. Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. Mol. Biol. Cell 14, 407–416 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zeng, L. et al. Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation. Mol. Cell. Biol. 20, 9212–9224 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fujikawa, K. et al. Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J. Exp. Med. 198, 1595–1608 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao, W.G., Byrne, M.H., Boyce, B.F. & Krane, S.M. Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice. J. Clin. Invest. 103, 517–524 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Miyamoto, T. et al. Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 98, 2544–2554 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Faccio, R., Novack, D.V., Zallone, A., Ross, F.P. & Teitelbaum, S.L. Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin. J. Cell Biol. 162, 499–509 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Faccio, R., Zou, W., Colaianni, G., Teitelbaum, S.L. & Ross, F.P. High dose M-CSF partially rescues the Dap12−/− osteoclast phenotype. J. Cell. Biochem. 90, 871–883 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Mocsai, A., Zhou, M., Meng, F., Tybulewicz, V.L. & Lowell, C.A. Syk is required for integrin signaling in neutrophils. Immunity 16, 547–548 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Tybulewicz, V.L.J., Ardouin, L., Prisco, A. & Reynolds, L.F. Vav1: a key signal transducer downstream of the TCR. Immunol. Rev. 192, 42–52 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Novack, D.V. et al. The IκB function of NF-κB2 p100 controls stimulated osteoclastogenesis. J. Exp. Med. 198, 771–781 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Duran, A. et al. The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev. Cell 6, 303–309 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. McHugh, K.P. et al. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J. Clin. Invest. 105, 433–440 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Faccio, R., Zallone, A., Ross, F.P. & Teitelbaum, S.L. c-Fms and the αvβ3 integrin collaborate during osteoclast differentiation. J. Clin. Invest. 111, 749–758 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaifu, T. et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111, 323–332 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Calle, Y. et al. WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption. Blood 103, 3552–3561 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Ridley, A.J. Rho GTPases and cell migration. J.Cell Sci. 114, 2713–2722 (2001).

    CAS  PubMed  Google Scholar 

  40. Ridley, A.J. Rho family proteins: coordinating cell responses. Trends Cell Biol. 11, 471–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Etienne-Manneville, S. & Hall, A. Rho GTPases in cell biology. Nature 420, 629–635 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, D. et al. The small GTP-binding protein, rho p21, is involved in bone resorption by regulating cytokskeletal organization in osteoclasts. J.Cell Sci. 108, 2285–2292 (1995).

    CAS  PubMed  Google Scholar 

  44. Fukuda, A. et al. Small GTP-binding protein Rac1 is involved in the cytoskeletal organization and activation of osteoclasts. J. Bone Miner. Res. 18, S79 (2003).

    Google Scholar 

  45. Turner, M. et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature. 378, 298–302 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Takeshita, S., Kaji, K. & Kudo, A. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J. Bone Miner. Res. 15, 1477–1488 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Lam, J. et al. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106, 1481–1488 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Feng, X. et al. A Glanzmann's mutation of the β3 integrin gene specifically impairs osteoclast function. J. Clin. Invest. 107, 1137–1144 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Faccio, R. et al. Localization and possible role of two different αvβ3 integrin conformations in resting and resorbing osteoclasts. J. Cell Sci. 115, 2919–2929 (2002).

    CAS  PubMed  Google Scholar 

  50. Ren, X.D., Kiosses, W.B. & Schwartz, M.A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 18, 578–585 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from US National Institutes of Health to S.L. Teitelbaum (AR32788, AR46523 and AR48853) and FP. Ross (AR48812, AR46852); American Cancer Society Award and Howard Hughes Medical Institute Institutional Research Award to W. Swat., and a grant from Associazione Spaziale Italiana and the European Space Agency (MAP Project AO-99-091) to A. Zallone.

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Author notes

  1. Keiko Fujikawa

    Present address: Department of Biochemistry, Graduate School of Medicine, Hokkaido University, N15 W7, Sapporo, 060-8638, Japan

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Roberta Faccio, Steven L Teitelbaum, Keiko Fujikawa, Jean Chappel, F Patrick Ross & Wojciech Swat

  2. Department of Orthopedic Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Roberta Faccio

  3. University of Bari, School of Medicine, P. zza G. Cesare 11, Bari, 70100, Italy

    Roberta Faccio & Alberta Zallone

  4. Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, UK

    Victor L Tybulewicz

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Supplementary information

Supplementary Figure 1

Expression of vav1, vav2 and vav3 genes in osteoclast-lineage cells. (PDF 47 kb)

Supplementary Figure 2

Expression of Vav isoforms in WT, Vav1ko, Vav3ko and Vav1/3ko OCs. (PDF 49 kb)

Supplementary Figure 3

Histomorphometric data of tibiae obtained from WT, Vav3ko, Vav3het, Sykhet and Vav3hetSykhet (Δhet) 6 weeks old mice. (PDF 73 kb)

Supplementary Figure 4

Bone resorptive capacity of WT, Vav3het, Vav3hetSykhet (Δhet), Vav3ko and Vav1/3ko OCs. (PDF 159 kb)

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Faccio, R., Teitelbaum, S., Fujikawa, K. et al. Vav3 regulates osteoclast function and bone mass. Nat Med 11, 284–290 (2005). https://doi.org/10.1038/nm1194

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