Downregulation of small GTPase Rab7 impairs osteoclast polarization and bone resorption

During skeletal growth and remodeling the mineralized bone matrix is resort ed by osteoclasts through the constant secretion of protons and proteases t o the bone surface. This relies on the formation of specialized plasma memb rane domains, the sealing zone and the ruffled border, and vectorial transp ortation of intracellular vesicles in bone-resorting osteoclasts. Here we s how that Rab7, a small GTPase that is associated with late endosomes, is hi ghly expressed and is predominantly localized at the ruffled border in bone -resorting osteoclasts. The decreased expression of Rab7 in cultured osteoc lasts by antisense oligodeoxynucleotides disrupted the polarization of the osteoclasts and the targeting of vesicles to the ruffled border. These impa irments caused a significant inhibition of bone resorption in vitro. The re sults indicate that the late endocytotic pathway is involved in the osteocl ast polarization and bone resorption and underscore the importance of Rab7 in osteoclast function.