Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Crawley, Australia.
Int J Biochem Cell Biol. 2012 Sep;44(9):1422-35. doi: 10.1016/j.biocel.2012.05.014. Epub 2012 May 29.
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.
液泡型 H(+)-ATP 酶（V-ATPase）质子泵是一种由至少 14 个亚基组成的大分子复合物，组织成两个功能域，V(1)和 V(0)。该复合物位于破骨细胞的皱褶缘质膜上，介导骨吸收过程中外周酸化以脱矿物质。从老鼠到人类的遗传研究表明，V-ATPase 亚基在与破骨细胞相关的疾病中（包括骨质增生症和骨质疏松症）起着关键作用。因此，V-ATPase 复合物是开发新型抗吸收剂的潜在分子靶点，这些药物可用于治疗溶骨性疾病。在这里，我们回顾了 V-ATPase 亚基的当前结构和功能，强调了它们在破骨细胞功能中的精细作用。此外，我们比较了几种不同类别的 V-ATPase 抑制剂对破骨细胞的特定抑制作用。了解破骨细胞 V-ATPase 的结构-功能关系可能会导致开发出针对破骨细胞的 V-ATPase 抑制剂，这些抑制剂可能成为治疗溶骨性疾病的替代疗法。
