A schematic representation of osteopontin/αvβ3 signaling in the regulation of prostate cancer cell migration. PC3 cells bind osteopontin through integrin αvβ3 in an RGD-dependent manner. Integrin αvβ3 increases Rho GTPase activity through down stream signaling pathway that involves RANKL  or tyrosine phosphorylation of several signaling molecules such as Src, PYK2, FAK, and p130Cas associated with integrin [10,64]. Rho activation increases CD44 surface expression [10,32] that resulted in the activation of MMP-9. The interaction of CD44 with MMP-9 on the cell surface may have a role in the degradation of ECM to facilitate cell migration. Bisphosphonates (BPs) inhibit CD44 surface interaction with MMP-9 either partially or completely. The signaling pathway and the target molecules that exhibit the inhibitory effects of BP treatment are indicated by dotted arrows and 'X'. A decrease (indicated by inverted red arrow) in CD44 surface expression, MMP-9 interaction with CD44 on the cell surface, MMP-9 secretion, and cell migration was observed in cells treated with BP. PC3/OPN cells treated with BPs reproduce the changes observed in PC3/SiRNA and PC3/OPN (RGA) The possible reason for these effects may be due to reduced αvβ3 -signaling in PC3/OPN (RGA) and PC3/SiRNA cells or targeting of αvβ3-signaling pathway by BPs.