Localization and possible role of two different alpha v beta 3 integrin conformations in resting and resorbing osteoclasts

Integrins are membrane receptors that mediate interactions between cells and the extracellular matrix. We recently showed that the osteoclast integrin α_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 α_vβ₃ accumulates in the motile areas of the plasma membrane. During bone resorption this conformation is prevalent in the ruffled membrane, whereas the 'basal' form of α_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 α_vβ₃ conformation in vitro. Preincubation with HGF or M-CSF induces a shift of conformation of α_vβ₃ in primary human osteoclasts (OCs) and in the osteoclast-like cell line (GCT 23). Activated integrin promotes osteoclast migration to the α_vβ₃ ligand osteopontin and enhances bone resorption. Thus, HGF and M-CSF modulate the α_vβ₃ conformational states required for osteoclast polarization and resorption. The capacity of growth factors to alter the affinity of α_vβ₃ toward its ligands offers a potential explanation for the diverse responses of osteoclasts to the same ligand.