FLNB基因通过CSF1R调控破骨细胞分化参与骨质疏松症发病的机制研究

骨质疏松症是一种复杂性状的遗传环境疾病，严重危害人民健康。突破传统的OPG-RANKL-RANK信号通路，寻找抗骨质疏松症治疗的新靶点，是亟待解决的科学难题。GWAS研究提示FLNB基因多态性与骨质疏松症相关。申请人曾报道FLNB基因突变可引起先天性骨骼畸形，近期已成功构建FLNB基因失活突变小鼠模型，Micro-CT显示小鼠骨小梁数目下降，RNA-seq提示破骨细胞前体细胞膜受体CSF1R显著上调。据此我们提出科学假设：FLNB失活可抑制CSF1R的内吞，促进破骨细胞分化，加快骨吸收，引起骨质疏松症发生。本课题计划基于已构建的小鼠模型，研究FLNB失活引起的骨微结构改变及FLNB调控CSF1R的分子机制，探索CSF1R对破骨细胞分化的影响，并通过干预CSF1R研究FLNB作为骨质疏松症治疗新靶点的可行性。基于骨质疏松症的新型病理生理机制的阐释，将有望为寻找骨质疏松症的干预靶点提供新思路。

Osteoporosis is a complex and polygene genetic disease, and a serious health hazard. It is urgent to get beyond the traditional OPG-RANKL-RANK signaling pathway and find new targets for osteoporosis treatment. Genome wide association studies (GWAS) reported that single nucleotide polymorphisms (SNP) in FLNB were associated with osteoporosis. We have previously reported that mutations in FLNB led to congenital skeletal deformity. We have recently established a mice model with an inactivation of FLNB, and found that the mice had a phenotype of decreased trabecular number in Micro-CT and an upregulated level of CSF1R, a membrane receptor of osteoclast precursor. We propose here a hypothesis that the loss of function of FLNB inhibits the endocytosis of CSF1R, promotes the differentiation of osteoclast, fastens the bone loss, and thus leads to the development of osteoporosis. We plan to use the established mice model to study the changes in bone microarchitecture in FLNB inactivation, the molecular mechanism of FLNB in regulating CSF1R, and the feasibility of FLNB as a potential marker of osteoporosis treatment by interfering CSF1R. We aim to illustrate the new pathophysiological mechanism of osteoporosis and provide basis for exploring new target for osteoporosis treatment.