Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts

Bone. 2006 Dec;39(6):1290-301. doi: 10.1016/j.bone.2006.06.012. Epub 2006 Sep 1.


Colony-stimulating factor-1 (CSF-1) induces osteoclast spreading that requires activation of c-Src and phosphatidyl inositol 3-kinase (PI3-K), both of which are recruited to activated c-Fms, the CSF-1 receptor. The present report provides evidence that the hemopoietic guanine nucleotide exchange factor (GEF), Vav, and its target GTPase, Rac, lie downstream from this initial signaling complex. CSF-1 treatment of osteoclast-like cells induced translocation of Vav to the plasma membrane, an increase in its phosphotyrosine content, and a concomitant decline in the amount of phosphoinositol 4,5-bisphosphate bound to Vav, changes known to induce Vav's GEF activity. CSF-1 induced the association of Vav and Rac and increased Rac's GTPase activity. CSF-1 also induced rapid translocation of Rac to the periphery of spreading neonatal rat osteoclasts where it co-localized primarily with Vav3 and to a lesser extent with Vav1. Wortmannin, an inhibitor of PI3-K, blocked CSF-1-induced Rac translocation and prevented CSF-1-induced spreading and actin reorganization in osteoclasts. CSF-1-induced osteoclast spreading was not significantly reduced in osteoclasts isolated from Vav1 knock-out mice and Vav1 knock-out mice had normal bone density. Microinjection of constitutively active Rac, but not constitutively active Cdc42 or RhoA, induced lamellipodia formation and osteoclast spreading, mimicking the effects of CSF-1. Dominant-negative Rac blocked CSF-1-induced osteoclast spreading, whereas neither dominant-negative Cdc42 nor C3, an inhibitor of RhoA, affected the response to CSF-1. These data demonstrate that Vav and Rac lie downstream from activated PI3-K in CSF-1-treated osteoclasts and that Rac is required for CSF-1-induced cytoskeletal remodeling in these cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Androstadienes / pharmacology
  • Animals
  • Biological Transport, Active / drug effects
  • Cells, Cultured
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Enzyme Inhibitors / pharmacology
  • Guanosine Triphosphate / metabolism
  • Humans
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Mice
  • Models, Biological
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding
  • Proto-Oncogene Proteins c-vav / metabolism*
  • Pseudopodia / drug effects
  • Rats
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Wortmannin
  • cdc42 GTP-Binding Protein / metabolism
  • rac GTP-Binding Proteins / metabolism*


  • Actins
  • Androstadienes
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-vav
  • Recombinant Proteins
  • Macrophage Colony-Stimulating Factor
  • Guanosine Triphosphate
  • Receptor, Macrophage Colony-Stimulating Factor
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins
  • Wortmannin