多发性腕骨跗骨骨质溶解综合征（MCTO）是以骨骼进行性破坏为特征的遗传性骨病，由转录因子MAFB转录激活结构域错义突变所致，相应分子发病机制仍未知。MAFB参与破骨细胞发育调控，是OPG/RANKL/RANK信号通路的负调控因子。课题组前期对MCTO患者的临床表型和基因型进行了系统分析，体外实验发现MAFB转录激活结构域错义突变并未影响其对OPG/RANKL/RANK信号通路的负调控作用。推测该结构域的错义突变可能以功能获得性机制促进破骨细胞前体细胞生成。本项目拟构建Mafb突变小鼠模型以及MCTO患者特异性诱导多能干细胞向破骨细胞定向分化的细胞模型，分析MCTO病理生理过程以及MAFB突变对破骨细胞发育和活性的影响，利用组学和分子生物学手段研究突变MAFB的作用靶点。以期阐明MCTO的分子发病机制，为该病靶向治疗奠定基础，并为破骨细胞异常相关骨病的发病机理及治疗研究提供新思路。

Multicentric carpotarsal osteolysis syndrome (MCTO) is a genetic skeletal disorder characterized by the progressive destruction of bone. It is caused by the missense mutations in the transactivation domain of the transcription factor MAFB. However,the molecular pathogenesis of MCTO remains unknown. MAFB is a negative regulator of the OPG/RANKL/RANK pathway and involves in the regulation of the osteoclast development. A systematic analysis of the phenotypes and genotypes of MCTO patients was conducted in our preliminary work.In vitro experiments showed that the missense mutations of the MAFB transactivation domain did not affect its negative regulation of OPG/RANKL/RANK pathway. It is hypothesized that the missense mutations of the MAFB transactivation domain may promote the formation of preosteoclast through the mechanism of gain of function. In this project, a Mafb mutant mouse model will be constructed. The induced pluripotent stem cells from MCTO patients will be established and differentiated into osteoclasts. The pathophysiological process of MCTO and the effects of MAFB mutation on the development and activity of osteoclasts will be studied. Omics-based methods combined with molecular biotechnology will be utilized to explore the target of the mutant MAFB. Thus we will elucidate the molecular mechanisms of MCTO, lay the foundation for the development of MCTO targeted therapy and provide new insights into the research of the pathogenesis and treatment of the skeletal disorders associated with abnormal osteoclasts.