V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption.
The vacuolar-type H(+)-ATPase (V-ATPase) proton pump is a macromolecular complex composed of at least 14 subunits organized into two functional domains, V(1) and V(0). The complex is located on the ruffled border plasma membrane of bone-resorbing osteoclasts, mediating extracellular acidification for bone demineralization during bone resorption. Genetic studies from mice to man implicate a critical role for V-ATPase subunits in osteoclast-related diseases including osteopetrosis and osteoporosis. Thus, the V-ATPase complex is a potential molecular target for the development of novel anti-resorptive agents useful for the treatment of osteolytic diseases. Here, we review the current structure and function of V-ATPase subunits, emphasizing their exquisite roles in osteoclastic function. In addition, we compare several distinct classes of V-ATPase inhibitors with specific inhibitory effects on osteoclasts. Understanding the structure-function relationship of the osteoclast V-ATPase may lead to the development of osteoclast-specific V-ATPase inhibitors that may serve as alternative therapies for the treatment of osteolytic diseases.
Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Crawley, Australia. dr.qinan@gmail.com
A
A
Qin
T S
TS
Cheng
N J
NJ
Pavlos
Z
Z
Lin
K R
KR
Dai
M H
MH
Zheng
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D025262:Vacuolar Proton-Translocating ATPases