alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology.
Osteoclasts, the sole bone-resorbing cells, arise by fusion and differentiation of monocyte/macrophage precursors. Matrix degradation requires adhesion of the osteoclast to bone, an integrin alphavbeta3-mediated event that also stimulates signals which polarize the cell and secrete resorptive molecules such as hydrochloric acid and acidic proteases. Two cytokines are necessary and sufficient for osteoclastogenesis, receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), both produced by mesenchymal cells in the bone marrow environment. M-CSF promotes survival and proliferation of osteoclast precursors. It also contributes to their differentiation and regulates the cytoskeletal changes that accompany bone resorption. Binding of M-CSF to c-Fms, its receptor, recruits adapter proteins and cytosolic kinases, thereby activating a variety of intracellular signals. We herein review how alphavbeta3 and M-CSF, alone and in concert, impact production, survival, and function of the osteoclast, thereby controlling skeletal mass. Signals from alphavbeta3 and/or c-Fms activate Syk and Vav3, originally defined by their function in lymphoid cells. Genetic depletion of either protein generates a strong bone phenotype, underscoring the promise of osteoimmunobiology.
Ross
F Patrick
FP
Washington University School of Medicine, St. Louis, MO 63110, USA. rossf@wustl.edu
Teitelbaum
Steven L
SL
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000502:physiology
D039302:Integrin alphaVbeta3; D051567:Proto-Oncogene Proteins c-vav; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020741:rho GTP-Binding Proteins