衰老引起成骨细胞数目减少和功能异常是导致老年性骨质疏松症（OP）的重要原因，但其机制尚不明确。我们预实验发现老年鼠骨组织中APT1表达下调，在骨髓基质干细胞（BMSC）中敲除APT1引起小鼠骨量减少，且体外敲降APT1抑制成骨分化和Wnt/β-catenin通路活性，提示APT1在骨稳态调节和OP发病中具有重要作用。本项目拟通过BMSC、前成骨和成骨细胞特异的APT1敲除小鼠和细胞模型，研究其对骨稳态和成骨细胞分化与功能的作用；通过分析APT1缺失对靶蛋白和Wnt/β-catenin等通路的影响，以及激活上述通路对其功能的挽救作用，阐明APT1发挥上述作用的分子机制；通过分析增龄对APT1及其靶蛋白的影响，以及APT1过表达或2-溴棕榈酸对OP的疗效，探讨APT1和棕榈酰化平衡在OP发病和治疗中的作用机制。本研究不仅将揭示OP新的发病机制，而且有望为其临床治疗和药物研发提供新靶标和新方向。

The age-dependent decline in number and function of osteoblasts is an important cause of age-related osteoporosis (OP). However, its underlying molecular mechanism is still not fully understood. In our preliminary study, we found that expression of APT1 was decreased in bone tissues of aged mice, that conditional knockout of APT1 in bone marrow stromal cells (BMSC) led to reduced bone mass, and that knockdown of APT1 in vitro suppressed osteoblast differentiation and the activity of Wnt/β-catenin signaling, suggesting that APT1 plays important roles in bone homeostasis and OP. In this project, we aim to: 1) investigate the roles of APT1 in regulating bone homeostasis, osteoblast differentiation and function, as well as its substrates and Wnt/β-catenin signaling, by using BMSC-, preosteoblast- and osteoblast-specific APT1 conditional knockout mice and their cells; 2) confirm that the above functions of APT1 is mediated by Wnt/β-catenin signaling by testing whether its activation can rescue the related defects in APT1-deficient cells; 3) explore the role and mechanism of APT1 and protein palmitoylation homeostasis in the pathogenesis and treatment of OP by examining the effects of aging on APT1 and its substrates, and the therapeutic outcomes of APT1 overexpression or 2-bromopalmitate on osteoporotic phenotypes in aged mice. This project will not only reveal a novel mechanism underlying OP, but also provide new therapeutic targets and directions for its treatment and drug development.