Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NF-kappa B activation

Mol Cell Biochem. 2006 Jan;281(1-2):55-61. doi: 10.1007/s11010-006-0333-y.

Abstract

Signaling by tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is essential for the differentiation of monocytes/macrophages into osteoclasts. We show here that TRANCE selectively activates Rac1, but not Rac2 in osteoclast precursors. Expression of a dominant interfering mutant of TNF receptor-associated factor (TRAF)6 blocks TRANCE-mediated Rac1 activation, indicating that Rac1 lies downstream of TRAF6. Osteoclast precursors expressing a dominant negative Rac1N17 are defective in TRANCE-induced IKK activation and IkappaBalpha degradation resulting in inhibition of NFkappaB-dependent reporter gene activity. In addition, Rac1 acts upstream of TAK1 to induce NF-kappaB activation and is required for the normal differentiation of osteoclast precursors. Thus, Rac1 may represent a key regulator for differentiation of osteoclasts through the activation of NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / physiology*
  • Cell Line, Transformed
  • MAP Kinase Kinase Kinases / physiology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B / physiology
  • Osteoclasts / cytology*
  • Osteoclasts / enzymology*
  • Osteoclasts / metabolism
  • RANK Ligand / physiology*
  • TNF Receptor-Associated Factor 6 / metabolism
  • rac1 GTP-Binding Protein / physiology*

Substances

  • NF-kappa B
  • RANK Ligand
  • TNF Receptor-Associated Factor 6
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • rac1 GTP-Binding Protein