酸分泌是破骨细胞骨质吸收的关键环节，通过液泡ATP酶介导的氢离子主动跨膜转运实现。酸分泌异常与骨硬化症、骨质疏松症、骨关节炎、Paget骨病、肿瘤骨转移等多种临床常见病相关。为深入分析破骨细胞酸分泌的分子生物学机制，我们前期通过基因突变、沉默等技术，体外研究阐明了液泡ATP酶亚单位Ac45在破骨细胞缝合区形成、细胞分化、细胞融合、酸化和骨吸收过程中重要的生物学功能。为进一步深入研究Ac45在破骨细胞酸化和骨吸收过程中的分子生物学机制，本研究构建了破骨细胞特异性的Ac45基因敲除小鼠，表型非常显著，将通过系统研究基因敲除小鼠的骨骼系统表型、破骨细胞酸化和骨吸收功能、溶酶体功能、液泡ATP酶蛋白复合体稳定性和各蛋白蛋白相互作用关系，进一步明确Ac45在破骨细胞液泡ATP酶介导的骨吸收过程中的分子作用机制，阐明Ac45在液泡ATP酶中的结构和功能特征，为临床靶向治疗破骨细胞相关疾病提供新的治疗。

Vacuolar-type H+-ATPases (V-ATPases) mediated extracellular acidification is crucial for bone demineralization during osteoclastic bone resorption. The importance of this proton pump is demonstrated by many genetic studies implicating them in osteoclast-related diseases such as osteopetrosis and osteoporosis. Our previous studies demonstrated that accessory subunit Ac45 interacts strongly with subunit a3 and the proteolipid c ring, both of which are critical for osteoclast acidification and bone resorption. Using gene overexpression system and siRNA-based approach, we showed that mutantion or targeted suppression of Ac45 impairs intracellular acidification and endocytosis, both are prerequisite for osteoclastic bone resorptive function in vitro. Interestingly, we find that knockdown of Ac45 also attenuates osteoclastogenesis owing to a reduced fusion capacity of osteoclastic precursor cells. In an effort to gain more detailed insights into the functional role of Ac45 in osteoclasts, we generated osteoclast-specific Ac45 conditional knockout mice using a Cre-LoxP system. The osteoclast specific Ac45 conditional knockout demonstrated severe ostepetosis. Thus, we propose that the conditional Ac45 mice will enable us to understand the molecular mechanisms of Ac45 during osteoclast bone resorption and bone remodeling, which may further direct clinical gene therapy in osteoclast related diseases.