The integrinsα _vβ₅ andα _vβ₃ are expressed reciprocally during murine osteoclastogenesis in vitro. Specifically, immature osteoclast precursors, in the form of bone marrow macrophages, contain exclusivelyα _vβ₅, surface expression of which declines with commitment to the osteoclast phenotype, while levels ofα _vβ₃ increase concomitantly. The distinct functional significance ofα _vβ₅ is underscored by the integrin’s capacity, unlikeα _vβ₃, to mediate both attachment and spreading on ligand, of marrow macrophages, suggesting α_vβ₅ negotiates initial recognition, by osteoclast precursors, of bone matrix. Northern analysis demonstrates changes in the two β-subunits, and not α_v, are responsible for these alterations. Treatment of early precursors with granulocyte-macrophage colony stimulating factor (GM-CSF) leads to alterations inβ ₃ and β₅ mRNA andα _vβ₅ andα _vβ₃, paralleling those occurring during osteoclastogenesis. Nuclear run-on and message stability studies demonstrate that while GM-CSF treatment of precursors alters β₅ transcriptionally, the changes in β₃ arise from prolonged mRNA t_1/2. Similar to GM-CSF treatment, the rate of β₅ transcription falls during authentic osteoclastogenesis. In contrast to cytokine-inducedα _vβ₃, however, that attending osteoclastogenesis reflects accelerated transcription of theβ ₃-subunit. Thus, while GM-CSF may participate in modulation of α_vβ₅ during osteoclast differentiation, signals other than those derived from the cytokine must regulate expression ofα _vβ₃.