The integrins avb5 and avb3 are expressed recip- rocally during murine osteoclastogenesis in vitro. Specifically, immature osteoclast precursors, in the form of bone marrow macrophages, contain exclusively avb5, surface expression of which de- clines with commitment to the osteoclast pheno- type, while levels of avb3 increase concomitantly. The distinct functional significance of avb5 is un- derscored by the integrin's capacity, unlike avb3 ,t o mediate both attachment and spreading on ligand, of marrow macrophages, suggesting avb5 negoti- ates initial recognition, by osteoclast precursors, of bone matrix. Northern analysis demonstrates changes in the two b-subunits, and not av, are responsible for these alterations. Treatment of early precursors with granulocyte-macrophage colony stimulating factor (GM-CSF) leads to alter- ations in b3 and b5 mRNA and avb5 and avb3, par- alleling those occurring during osteoclastogen- esis. Nuclear run-on and message stability studies demonstrate that while GM-CSF treatment of pre- cursors alters b5 transcriptionally, the changes in b3 arise from prolonged mRNA t1/2. Similar to GM-CSF treatment, the rate of b5 transcription falls during authentic osteoclastogenesis. In contrast to cytokine-induced avb3, however, that attending osteoclastogenesis reflects accelerated transcrip- tion of the b3-subunit. Thus, while GM-CSF may participate in modulation of avb5 during osteoclast differentiation, signals other than those derived from the cytokine must regulate expression of avb3. (Molecular Endocrinology 12: 1955-1962, 1998)