The integrins α(v)/β3 and α(v)β3 are expressed reciprocally during murine osteoclastogenesis in vitro. Specifically, immature osteoclast precursors, in the form of bone marrow macrophages, contain exclusively α(v)/β5, surface expression of which declines with commitment to the osteoclast phenotype, while levels of α(v)/β3 increase concomitantly. The distinct functional significance of α(v)/β5 is underscored by the integrin's capacity, unlike α(v)β3, to mediate both attachment and spreading on ligand, of marrow macrophages, suggesting α(v)β5 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 in β3 and β5 mRNA and α(v)β5 and α(v)β3, 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-induced α(v)β3, however, that attending osteoclastogenesis reflects accelerated transcription of the β3-subunit. Thus, while GM-CSF may participate in modulation of α(v)β5 during osteoclast differentiation, signals other than those derived from the cytokine must regulate expression of α(v)β3.