Xu J, Cheng T, Feng H T, Pavlos N J, Zheng M H
Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands, Australia.
Histol Histopathol. 2007 Apr;22(4):443-54. doi: 10.14670/HH-22.443.
Excessive activity of osteoclasts becomes manifest in many common lytic bone disorders such as osteoporosis, Paget's disease, bone aseptic loosening and tumor-induced bone destruction. Vacuolar proton pump H+-adenosine triphosphatases (V-ATPases), located on the bone-apposed plasma membrane of the osteoclast, are imperative for the function of osteoclasts, and thus are a potential molecular target for the development of novel anti-resorptive agents. To date, the V-ATPases core structure has been well modeled and consists of two distinct functional domains, the V1 (A, B1, B2, C1, C2, D, E1, E2, F, G1, G2, G3, and H subunits) and V0 (a1, a2, a3, a4, d1, d2, c, c' e1, e2 subunits) as well as the accessory subunits ac45 and M8-9. However, the exact configuration of osteoclast specific V-ATPases remains to be established. Inactivation of subunit a3 leads to osteopetrosis in both mice and man because of non-functional osteoclasts that are capable of acidifying the extracellular resorption lacuna. On the other hand, inactivation of subunits c, d1 and ac45 results in early embryonic lethality, indicating that certain subunits, such as a3, are more specific to osteoclast function than others. In osteoclasts, V-ATPases also cooperate with chloride channel protein CLC-7 to acidify the resorption lacuna. In addition, development of V-ATPases inhibitors such as bafilomycin A1, SB 242784 and FR167356 that selectively target osteoclast specific V-ATPases remains a challenge. Understanding the molecular and cellular mechanisms by which specific subunits of V-ATPase regulate osteoclast function might facilitate the development of novel and selective inhibitors for the treatment of lytic bone disorders. This review summarizes recent research developments in V-ATPases with particular emphasis on osteoclast biology.
破骨细胞的过度活跃在许多常见的溶骨性骨疾病中表现明显，如骨质疏松症、佩吉特病、骨无菌性松动和肿瘤诱导的骨破坏。位于破骨细胞骨附着质膜上的液泡质子泵H⁺ - 三磷酸腺苷酶（V - ATP酶）对破骨细胞的功能至关重要，因此是开发新型抗吸收剂的潜在分子靶点。迄今为止，V - ATP酶的核心结构已得到很好的建模，由两个不同的功能域组成，即V1（A、B1、B2、C1、C2、D、E1、E2、F、G1、G2、G3和H亚基）和V0（a1、a2、a3、a4、d1、d2、c、c'、e1、e2亚基）以及辅助亚基ac45和M8 - 9。然而，破骨细胞特异性V - ATP酶的确切构型仍有待确定。亚基a3的失活会导致小鼠和人类出现骨硬化症，因为无功能的破骨细胞无法酸化细胞外吸收腔隙。另一方面，亚基c、d1和ac45的失活会导致早期胚胎致死，这表明某些亚基，如a3，比其他亚基对破骨细胞功能更具特异性。在破骨细胞中，V - ATP酶还与氯通道蛋白CLC - 7协同作用以酸化吸收腔隙。此外，开发选择性靶向破骨细胞特异性V - ATP酶的V - ATP酶抑制剂，如巴弗洛霉素A1、SB 242784和FR167356，仍然是一个挑战。了解V - ATP酶的特定亚基调节破骨细胞功能的分子和细胞机制可能有助于开发用于治疗溶骨性骨疾病的新型选择性抑制剂。本综述总结了V - ATP酶的最新研究进展，特别强调破骨细胞生物学。
