Integrins are membrane receptors that mediate interactions between cells and the extracellular matrix. We recently showed that the osteoclast integrinα vβ3 exists in two different conformations,so-called `basal' and `activated', with each exhibiting a distinct function. In this study we demonstrate that, in non-resorbing osteoclasts, the`activated' form of αvβ3 accumulates in the motile areas of the plasma membrane. During bone resorption this conformation is prevalent in the ruffled membrane, whereas the `basal' form ofα vβ3 is also present in the sealing zone. Moreover, hepatocyte growth factor (HGF) and macrophage colony stimulating factor (M-CSF), two molecules involved in osteoclastogenesis and osteoclast survival, modulate αvβ3 conformation in vitro. Preincubation with HGF or M-CSF induces a shift of conformation ofα vβ3 in primary human osteoclasts (OCs) and in the osteoclast-like cell line (GCT 23). Activated integrin promotes osteoclast migration to the αvβ3 ligand osteopontin and enhances bone resorption. Thus, HGF and M-CSF modulate theα vβ3 conformational states required for osteoclast polarization and resorption. The capacity of growth factors to alter the affinity of αvβ3 toward its ligands offers a potential explanation for the diverse responses of osteoclasts to the same ligand.