Molecular dissection of V-ATPase proton pump: a therapeutic target for osteolytic disease

[Truncated abstract] V-ATPases are multisubunit complexes composed of at least 14 subunits organized into two functional domains, V1 and V0. Subunits A-H form the peripheral V1 domain that drives ATP hydrolysis to energize and initiate the rotation of the V0 domain. Comparatively, subunits a, c, c′, c″, d and e, in a stoichiometry of a1d1c4-5c′1c″1e1, form the membrane bound V0 domain which utilizes the energy generated by the V1 domain to translocate protons across the membrane. In addition, mammalian V-ATPase complexes also consist of two further accessory subunits, Ac45 and M8-9, with their functions still unclear. In osteoclasts, V-ATPases plays a critical role in acidifying the extracellular space necessary for osteoclastic bone resorption, the specialized function that can only be carried out by osteoclasts. Osteoclastic bone resorption is a multi-step process involving at least four continuous stages: (1) osteoclast attachment to the bone surface; (2) plasma membrane polarization to form the resorptive organelle; (3) bone degradation and resorption; and (4) endocytosis of degraded bone matrix and transcytotic transport to the functional secretory domain. Acidification of the resorptive lacunae to a pH of ~4.5 is facilitated by the huge density of V-ATPases populating the ruffled border and initiates the demineralization of the bone matrix. There is increasing evidence that mutation, knockdown or knockout of V-ATPase subunits causes osteoclast dysfunction leading to osteopetrosis in both mice and human. Furthermore, V-ATPase inhibitors are capable of blocking osteoclastic bone resorption in vitro and preventing bone loss in vivo. Thus, V-ATPase presents as a potential therapeutic target for osteoclast-related diseases.