Nordic Bioscience A/S, Bone Biology and Biomarkers, Denmark.
Curr Protein Pept Sci. 2012 Mar;13(2):141-51. doi: 10.2174/138920312800493133.
The unique ability of the osteoclasts to resorb the calcified bone matrix is dependent on secretion of hydrochloric acid. This process is mediated by a vacuolar H+ ATPase (V-ATPase) and a chloride-proton antiporter. The structural subunit of the V-ATPase, a3, is highly specific for osteoclasts, and mutations in a3 lead to infantile malignant osteopetrosis, a phenomenon characterized by increased bone mass, an increased number of non-resorbing osteoclasts, and a complete lack of bone resorption. Importantly, these individuals have normal or even increased osteoblast numbers and bone formation suggesting that the osteoclasts, but not their resorptive capability, relay an anabolic signal, and, hence, that bone formation can be uncoupled from bone resorption when the a3 subunit is eliminated by mutations, or possibly by pharmacological intervention. The pharmacological profile of the a3 subunit as a highly specific target with a mode of action profile augmenting uncoupling and sustained bone formation, as derived from osteopetrotic patients and mice, highlights the relevance of the V-ATPase in future osteoporosis drug development. However, as illustrated by numerous attempts at developing specific inhibitors of the osteoclastic V-ATPase it is a very difficult target to work with, and an inhibitor possessing the desired profile remains elusive, although highly promising approaches recently have been launched.
破骨细胞能够重吸收钙化的骨基质的独特能力依赖于盐酸的分泌。这个过程由液泡 H+ATP 酶 (V-ATPase) 和氯离子-质子反向转运体介导。V-ATPase 的结构亚基 a3 对破骨细胞具有高度特异性，a3 的突变导致婴儿恶性成骨不全症，其特征是骨量增加、非吸收性破骨细胞数量增加和完全缺乏骨吸收。重要的是，这些个体的成骨细胞数量正常甚至增加，骨形成增加，这表明破骨细胞，但不是它们的吸收能力，传递了一种合成代谢信号，因此，当 a3 亚基被突变或可能通过药物干预消除时，骨形成可以与骨吸收解偶联。从成骨不全症患者和小鼠中得出的 a3 亚基作为一个高度特异性靶点的药物特征，其作用模式增强了解偶联和持续的骨形成，突出了 V-ATPase 在未来骨质疏松症药物开发中的相关性。然而，正如许多试图开发破骨细胞 V-ATPase 特异性抑制剂的尝试所表明的那样，这是一个非常难以处理的靶点，尽管最近已经提出了非常有希望的方法，但仍然缺乏具有所需特征的抑制剂。
