MPP7通过YAP调控WNT/β-catenin通路影响成骨分化和骨量生成的作用机制研究

One of the important reasons for osteoporosis is the decrease and dysfunction of osteoblasts due to genetic development factors. Multiple genome-wide association analyses (GWAS) identified numberous of newly discovered bone mineral density-related gene sequence variants, and the rs4317882 locus of MPP7 was found to be associated with low bone density. The specific molecular mechanism by which MPP7 leads to lower bone density is not clear. Previous studies in this project group showed that MPP7 is expressed in human and mouse osteoblasts, and silencing MPP7 can inhibit osteogenic differentiation. Data revealed that MPP7 can bind and stabilize YAP, induce its entry into the nucleus, and promote the nucleus translocation of β-catenin and promotes osteogenic differentiation and bone mass production. We hypothesized that MPP7 may affect osteogenic differentiation and bone formation through YAP-mediated WNT/β-catenin pathway. We intend to use the conventional MPP7 knockout mice and osteoblast lineages MPP7 knock out mice, to elucidate the role of MPP7 in osteogenic differentiation and bone formation; at the molecular level, this project aim at studying the molecular mechanism of MPP7 regulation of osteogenic differentiation and bone formation. This project will deepen our understanding of abnormal bone development and osteoporosis and provide new therapeutic targets for osteoporosis and bone development disorders.

遗传因素导致成骨细胞减少以及骨量形成障碍是骨质疏松症发病的重要原因之一。通过多项全基因组关联性分析（GWAS），新发现了许多和骨密度相关基因序列变异，其中发现棕榈酰化膜蛋白7（MPP7）rs4317882位点突变同低骨密度相关，而MPP7影响骨密度的具体分子机制尚不明确。本项目组前期研究显示，MPP7在人及小鼠成骨细胞中表达，沉默MPP7能够阻抑成骨分化，MPP7可结合并稳定YAP（Yes相关蛋白），诱导其入核，同时促进β-catenin入核，促进成骨分化。我们推测：MPP7可能通过YAP调控WNT/β-catenin通路影响成骨分化和骨形成。我们拟在整体水平，利用全身和成骨细胞谱系特异敲除MPP7的小鼠，阐述MPP7在成骨分化及骨形成中的作用；在分子水平，研究MPP7调控成骨分化及骨形成的分子机制。本项目将加深我们对骨发育异常、骨质疏松的理解，为骨质疏松症及骨发育障碍提供新的治疗靶点。

遗传因素导致成骨细胞减少以及骨量形成障碍是骨质疏松症发病的重要原因之一。通过多项全基因组关联性分析（GWAS），新发现了许多和骨密度相关基因序列变异，其中发现棕榈酰化膜蛋白7（MPP7）rs4317882位点突变同低骨密度相关，而MPP7影响骨密度的具体分子机制尚不明确。我们在整体水平，利用全身和成骨细胞谱系特异敲除MPP7的小鼠，阐述MPP7在成骨分化及骨形成中的作用；在分子水平，研究MPP7调控成骨分化及骨形成的分子机制。本项目研究显示，MPP7敲除后，小鼠体内的骨量骨密度下降，成骨能力下降。MPP7在人及小鼠成骨细胞中表达，过表达MPP7能够促进成骨分化，MPP7可结合并稳定YAP，诱导其入核，同时促进β-catenin入核，促进成骨分化。综上所述：本项目发现MPP7可能通过YAP调控WNT/β-catenin通路影响成骨分化和骨形成。本项目将加深我们对骨发育异常、骨质疏松的理解，为骨质疏松症及骨发育障碍提供新的治疗靶点。