Nell-1通过RACK1调控Wnt信号通路抗骨质疏松的作用机制研究

寻找新的骨质疏松症治疗靶点意义重大，其中促进骨形成是关键切入点。Nell-1作为骨生长因子可以调控成骨细胞的分化与矿化，是骨质疏松症潜在的调控因子与治疗靶标，但具体作用机制尚不明确。本项目前期研究证实，在骨质疏松患者血清中Nell-1表达量显著低于正常人群；Nell-1干预可以促进成骨细胞分化。机制研究方面，我们利用蛋白质组研究发现Wnt通路受Nell-1调控。进一步IP-MS实验发现支架蛋白RACK1与Nell-1相互作用，既往研究也提示RACK1是Wnt通路的负调控因子。因此，我们提出假设：Nell-1通过拮抗RACK1，参与Wnt通路的活化促进成骨分化。本课题基于前期临床表型及蛋白组数据，拟在分子、细胞及模式动物三个层面研究Nell-1促进成骨分化及抗骨质疏松症的分子机制，通过干预实验探讨Nell-1作为骨质疏松治疗靶点的可行性，进一步为抗骨质疏松的靶向药物开发提供理论依据。

It is of great significance to find new therapeutic targets for osteoporosis, and the promotion of osteogenic differentiation is the key entry point. Nell-1, as a bone growth factor, can regulate the differentiation and mineralization of osteoblasts. It is a potential regulator and therapeutic target of osteoporosis, but the specific mechanism remains elusive. The preliminary study of this project confirmed that the expression of Nell-1 in the serum of osteoporosis patients was significantly lower than that of the normal population. Nell-1 intervention could promote osteoblast differentiation. In terms of mechanism research, quantitative proteomics was approached and found that the Wnt pathway was regulated by Nell-1. Further IP-MS experiment found that the scaffold protein RACK1 was a binding protein of Nell-1. Based on previous studies, it is suggested that RACK1 is a negative regulator of the Wnt pathway. Therefore, we put forward the hypothesis: Nell-1 promotes osteogenic differentiation by antagonizing RACK1 and participating in the activation of the Wnt pathway. Based on clinical phenotype and proteomic data, this project intends to investigate the molecular mechanism of Nell-1 by which promotes osteogenic differentiation and anti-osteoporosis at the molecular, cellular and model animal levels. Moreover, we are proposed to explore the possibility of Nell-1 as a new target in osteoporosis by intervention experiments. This project could further provide a theoretical basis for the development of targeted drugs in anti-osteoporosis.