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Tyrosines 559 and 807 in the Cytoplasmic Tail of the Macrophage Colony-Stimulating Factor Receptor Play Distinct Roles in Osteoclast Differentiation and Function

Departments of Pathology and Immunology, Washington University School of Medicine (X.F., S.T., N.N., S.W., S.L.T., F.P.R.), St. Louis, Missouri 63110; and Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry (N.N.), Okayama 700-8558, Japan

Address all correspondence and requests for reprints to: F. Patrick Ross, Ph.D., Washington University School of Medicine, Department of Pathology, Barnes-Jewish Hospital North, Mailstop 90-31-649, 216 South Kingshighway, St. Louis, Missouri 63110. E-mail: rossf{at}medicine.wustl.edu.

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 B (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 Y⁶⁹⁷F, Y⁷⁰⁶F, Y⁷²¹F, and Y⁹²¹F 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 Y⁵⁵⁹F generate fewer OCs, whereas theY807F mutant is incapable of osteoclastogenesis. Finally, although mature OCs expressing Y⁵⁵⁹F 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.

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