GRANULOCYTE MACROPHAGE-COLONY-STIMULATING FACTOR RECIPROCALLY REGULATES ALPHA(V)-ASSOCIATED INTEGRINS ON MURINE OSTEOCLAST PRECURSORS

The integrins alpha(v)beta(5) and alpha(v)beta(3) are expressed recipr ocally during murine osteoclastogenesis in vitro. Specifically, immatu re osteoclast precursors, in the form of bone marrow macrophages, cont ain exclusively alpha(v)beta(5), surface expression of which declines with commitment to the osteoclast phenotype, while levels of alpha(v)b eta(3) increase concomitantly. The distinct functional significance of alpha(v)beta(5) is underscored by the integrin's capacity, unlike alp ha(v)beta(3), to mediate both attachment and spreading on ligand, of m arrow macrophages, suggesting alpha(v)beta(3), negotiates initial reco gnition, by osteoclast precursors, of bone matrix, Northern analysis d emonstrates changes in the two beta-subunits, and not alpha(v), are re sponsible for these alterations. Treatment of early precursors with gr anulocyte-macrophage colony stimulating factor (GM-CSF) leads to alter ations in beta(3) and beta(5) mRNA and alpha(v)beta(5) and alpha(v)bet a(3), paralleling those occurring during osteoclastogenesis. Nuclear r un-on and message stability studies demonstrate that while GM-CSF trea tment of precursors alters beta(5) transcriptionally, the changes in b eta(3) arise from prolonged mRNA t(1/2). Similar to GM-CSF treatment, the rate of beta(5) transcription falls during authentic osteoclastoge nesis. In contrast to cytokine-induced alpha(v)beta(3), however, that attending osteoclastogenesis reflects accelerated transcription of the beta(3)-subunit, Thus, while GM-CSF may participate in modulation of alpha(v)beta(5) during osteoclast differentiation, signals other than those derived from the cytokine must regulate expression of alpha(v)be ta(3).