Tyrosines 559 and 807 in the cytoplasmic tail of the macrophage colony-stimulating factor receptor play distinct roles in osteoclast differentiation and function

Academic Article

Abstract

  • Osteoclast (OC) differentiation requires that precursors, such as macrophage colony-stimulating factor (M-CSF)-dependent bone marrow macrophages, receive signals transduced by receptor activator of nuclear factor κB (RANK) and c-Fms, receptors for RANK ligand (RANKL) and M-CSF, respectively. Activated c-Fms autophosphorylates cytoplasmic tail tyrosine residues, which, by recruiting adaptor molecules, initiate specific signaling pathways. To identify which tyrosine residues are involved in c-Fms signaling in primary cells, we retrovirally transduced M-CSF-dependent bone marrow macrophages with a chimera comprising the external domain of the erythropoietin (Epo) receptor linked to the transmembrane and cytoplasmic domains of c-Fms. Transduced cells differentiate into bone-resorbing osteoclasts when treated with RANKL and either M-CSF or Epo, confirming that both endogenous and chimeric receptors transmit osteoclastogenic signals. Cells expressing chimeric receptors with Y F, Y F, Y F, and Y F single point mutations generate normal numbers of bone-resorbing OCs, with normal bone-resorbing activity when treated with RANKL and Epo. In contrast, those expressing Y F generate fewer OCs, whereas the Y F mutant is incapable of osteoclastogenesis. Finally, although mature OCs expressing Y F exhibit impaired bone resorption, those bearing Y807F do not. Thus, we have identified specific tyrosine residues in the cytoplasmic tail of c-Fms that are critical for transmitting M-CSF-initiated signals individually required for OC formation or function, respectively. 697 706 721 921 559 807 559
  • Published In

  • Endocrinology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Feng X; Takeshita S; Namba N; Wei S; Teitelbaum SL; Ross FP
  • Start Page

  • 4868
  • End Page

  • 4874
  • Volume

  • 143
  • Issue

  • 12