破骨细胞是人体内唯一具有骨吸收功能的细胞,其功能异常与骨质疏松症、骨关节炎、肿瘤骨破坏等疾病息息相关。我们前期研究发现Furin基因在破骨细胞前体细胞内高表达，且随着破骨细胞分化成熟表达增高;进一步构建破骨细胞特异性Furin基因条件性敲除小鼠，发现破骨细胞内敲除Furin基因后可导致小鼠表现为骨硬化表型;体外研究发现Furin基因敲除可降低破骨细胞骨吸收深度，提示Furin在破骨细胞骨吸收过程中发挥重要功能。此外，Furin基因敲除后，破骨细胞内酸分泌相关蛋白Ac45蛋白表达下降。结合上述前期工作，本研究将系统分析Furin条件性基因敲除的骨骼表型，破骨细胞骨吸收功能，Furin对Ac45及其他底物蛋白的调控功能，并进一步研究Furin特异性抑制剂对卵巢切除小鼠骨丢失的保护作用，以期明确Furin基因在破骨细胞骨吸收中的分子机制，为临床治疗破骨细胞相关疾病提供新的分子靶点。

Osteoclasts are the only cells that are capable of bone resorption. The dysfunction of osteoclasts are closely related with diseases such as osteoporosis, osteoarthritis and tumor induced osteolysis. Using microarray analysis and quantitative proteomic (iTRAQTM) profiling between OCs and macrophages, we have systematically screened for novel molecules that are regulated in OCs during RANKL (receptor activator of NF-κB ligand)-mediated differentiation. Among the candidates identified, we uncovered a cluster of genes encoding nine members of a convertase protein family that regulate proteolytic maturation of proproteins. Among these, furin was identified as the most i) abundant and ii) RANKL-responsive isoform expressed in OCs. Further preliminary studies indicate that OC-specific Cathepsin K-Cre/loxP furin cKO mice exhibit an increased bone mass phenotype with characteristics most consistent with osteopetrosis. The bone resorption function was impaired after furin knockout. In addition, the amount of V-ATPase Ac45 subunit decreased after furin knockout. Based on these novel and interesting observations, we hypothesize that furin regulates bone homeostasis and osteoclastic bone resorption through its intimate association with the v-ATPase accessory subunit Ac45. To address this we Aim to: 1) Comprehensively characterize the bone phenotype of Cathepsin K-Cre/loxP furin cKO mice;2) Investigate the physiological role of furin in OC-mediated bone resorption in vitro; 3) Determine the role of furin in the maturation of v-ATPase accessory subunit Ac45 in OCs; 4) Examine the role of furin in animal models of osteoporosis induced by OVX. 5) Investigated the potential protective effect of furin specific inhibitor on OVX mice. This study will potentially identify novel molecular targets for osteoclast related diseases.