Lats1促进破骨细胞分化在骨量维持中的作用和机制研究

Hippo信号关键激酶Lats1在组织稳态维持中具有重要的角色，但其在破骨细胞分化和骨量维持中的作用却不得而知。我们前期的研究发现，Lats1 KO小鼠呈现破骨前体细胞数目增加但成熟的破骨细胞数目减少，提示Lats1正向调控破骨细胞的分化，这与文献报道的Hippo信号其它分子包括Mst2、Rassf2、Yap1反向调控破骨细胞分化截然相反。为此，我们着眼于NF-κB信号并发现，Lats1介导RANKL(TNF-α)诱导的NF-κB信号激活，而且Lats1可能在Ser37位点直接磷酸化ELKS1并稳定ELKS1蛋白而激活NF-κB信号。以此为据，本项目拟进一步利用骨髓来源的巨噬细胞、巨噬细胞系和一系列的基因修饰小鼠模型，深入阐明Lats1在破骨细胞分化和骨量维持中的重要角色及可能的分子机制。通过本项目的研究，将为骨组织稳态的分子调控提供新的理论，也将为骨质疏松症的药物治疗提供新的靶标。

Lats1 is a key kinase in mediating Hippo signaling and plays a pivotal role in the maintenance of tissue homeostasis. However, whether Lats1 is important in the osteoclast function and bone homeostasis remains unknown. Our preliminary data indicate that Lats1 mediates RANKL(TNF-α)-induced activation of NF-κB signaling, whereas systemic deletion of Lats1 causes the increased bone volumes, increased number of osteoblasts and pre-osteoclasts, but the decreased number of mature osteoclasts. Moreover, Lats1 loss-of-function in pre-osteoclasts enhances the bone volume, decreases the differentiation and absorption of pre-osteoclasts. Based on these findings, we are going to investigate further the roles of Lats1 in osteoclast differentiation and function in the bone resorptive microenvironments by using molecular biological approaches, cell line of macrophage, primary macrophages, and wild-type and Lats1 conditional knock-out mice. This project will elucidate the detailed role and mechanism underlying Lats1-mediated bone resorption and formation and will possibly shed light on the mechanism governing bone homeostasis and the pathogenesis of osteoporosis.