破骨细胞是体内唯一具有骨吸收功能的细胞，其数量与功能的变化与骨丢失密切相关。在上一个国家自然青年基金支持下，研究发现ENU诱导Rc3h1基因全身突变小鼠出现了骨量下降，骨组织中RANKL：OPG比值升高且破骨细胞增多；体外实验显示Rc3h1基因突变小鼠破骨细胞对RANKL诱导的敏感性增高，骨吸收能力增强；Rc3h1编码的异常Roquin蛋白促进破骨细胞MAPK通路ERK磷酸化，但其与TRAF6无偶联关系。本课题组首次发现Rc3h1基因影响破骨细胞分化和骨吸收，小鼠表型为骨丢失。为深入阐明Rc3h1在破骨细胞中的作用，将利用Rc3h1基因破骨细胞条件性敲除小鼠，通过对其的骨表型、破骨细胞分化、骨吸收等方面研究，探索Rc3h1基因编码的E3泛素连接酶Roquin蛋白与AMPK及自噬溶酶体之间的相互作用，以了解Rc3h1在破骨细胞分化及骨吸收中的分子机制，为临床治疗破骨细胞相关疾病提供基础依据。

Osteoclasts is the only cells with bone resorption function in the body, and changes to their numbers and functions are closely related to bone loss. With the supporting data of the previous National Natural Youth Fund, we found that ENU induced a decrease in bone mass, an increase in the ratio of RANKL:OPG and an increase in the number of osteoclasts in the Rc3h1 gene knockout mice. In vitro experiments showed that osteoclasts with Rc3h1 gene mutation showed increased sensitivity to RANKL induction and enhanced bone resorption activities. The abnormal Roquin protein encoded by mutated Rc3h1 promoted the phosphorylation of ERK in the osteoclastic MAPK signaling pathway, however the immunoprecipitation assay showed that there was no direct interaction between Roquin protein and TRAF6.For the first time, our group found that Rc3h1 gene affected osteoclast differentiation and bone resorption, and the mutation mouse model presented a phenotype of bone loss. To further clarify the role of Rc3h1 gene in osteoclast, we will use a mouse model of conditional knockout of Rc3h1 gene in osteoclast, by which we will study its bone phenotype, serum, osteoclast differentiation, bone resorption, etc. We would also explore the interaction between Roquin protein and AMPK as well as autophagy lysosome in order to understand the molecular mechanism of Rc3h1 gene in osteoclast differentiation and bone resorption, hence to provide the basis for clinical treatment of osteoclast-related diseases.