Fstl1通过BMP信号通路调控成骨细胞分化和功能在骨质疏松症中的作用机制研究

How to promote the function of osteoblasts is one of the crucial problems in the treatment of osteoporosis. Our previous study showed that the expression of Follistatin-like 1 (Fstl1) was significantly increased in osteoporosis patients and ovariectomised (OVX) animal models，haploinsufficiency of Fstl1 alleviated OVX-induced osteoporosis in mice. Moreover, Fstl1 inhibited the differentiation of osteoblasts in vitro. All these results suggested that Fstl1 might play an important role in osteoporosis. However, the function and mechanism of Fstl1 in osteoporosis need to be further confirmed. The aim of this study is to examine how Fstl1 play a role in osteoporosis by regulating the differentiation and function of osteoblasts and to explore the underlying cellular and molecular mechanisms. This study will identify the relationship between Fstl1 and osteoporosis in human and animal models, reveal the mechanism in cell model and mouse genetic model by generation of osteoblast-lineage cell-specific Fstl1 conditional knock out mice, and examine the therapeutic effect of Fstl1 neutralizing antibody on osteoporosis. This study is significant for understanding of the mechanism of osteoporosis，and will provide theoretical basis and novel targets for osteoporosis.

如何促进成骨细胞的骨形成是骨质疏松治疗面临的关键问题。本项目前期研究发现，在骨质疏松症患者及动物模型中滤泡素抑制素样蛋白1（Fstl1）表达升高，在小鼠中单倍敲除Fstl1可明显减轻卵巢切除诱导的骨质疏松症，在体外Fstl1可抑制BMP4诱导的成骨细胞分化，提示Fstl1参与调控骨质疏松症的发生，但具体作用机制有待证实。本项目旨在研究Fstl1如何通过调控成骨细胞的分化和功能参与骨质疏松症的病理过程及其细胞分子机制：在人群及动物水平明确Fstl1与骨质疏松症发生发展的相关性；通过构建在成骨细胞及其前体细胞中特异性敲除Fstl1的条件性敲除小鼠，利用小鼠遗传模型和体外原代细胞培养体系研究Fstl1对骨质疏松症的作用机制；评估Fstl1中和性抗体对骨质疏松症的治疗作用。本项目的实施有助于阐明骨质疏松症新的致病机制，为骨质疏松症的早期预测、诊断以及靶向治疗提供新思路和理论依据。

本项目前期研究发现，在骨质疏松症患者及动物模型中，滤泡素抑制素样蛋白1（Fstl1）与骨质疏松的发生有关，但具体作用机制有待证实。本项目旨在研究Fstl1如何通过调控成骨细胞的分化和功能参与骨质疏松症的病理过程及其细胞分子机制，主要研究以下内容：1.Fstl1与骨质疏松发生的相关性；2.Fstl1敲降对小鼠骨质疏松的影响；3.Fstl1对前成骨细胞系MC3T3-E1增殖、凋亡、分化的影响。研究发现：1.在临床患者水平，FSTL1在女性骨质疏松病人外周血中表达水平下降；FSTL1与女性骨松患者血清中骨形成指标PINP、骨吸收指标β-CTX负相关；2.在动物模型水平，Fstl1敲降使OVX骨质疏松小鼠骨量下降更多；Fstl1敲降成年雄鼠中股骨组织内的骨量下降；Fstl1敲降自然衰老骨质疏松模型中股骨组织内的骨量下降；3.在细胞水平，Fstl1对MC3T3-E1增殖和凋亡无显著影响；Fstl1可促进MC3T3-E1向成骨细胞分化。本研究加深了对骨质疏松发病机制的认识，为骨质疏松症的治疗提供潜在药物靶点，为骨质疏松症高风险人群的筛查、疾病诊断、分型和治疗等方面进行精准医疗干预提供了重要的实验数据和理论依据。.