骨质疏松症是在老年人口中高发的、以骨量减少为特征的骨代谢疾病。由于骨髓间充质干细胞（MSC）成骨/成脂分化命运的“此消彼长”，以及骨髓脂肪组织（MAT）对骨代谢的抑制作用，MAT和骨量多呈现负相关的关系。目前MAT形成的分子机制尚不明确，骨骼微环境对MAT的调控亦缺少系统性研究，故解析MAT的形成机制具有重要的临床和科学意义。已知转录因子Cbfβ在成骨前体细胞中的缺陷导致小鼠骨量减少、MAT增加。本研究拟以成熟成骨细胞和骨细胞特异性Cbfβ敲除小鼠为模型，研究成骨细胞和骨细胞的旁分泌信号对MAT形成的调控机理。本研究拟①通过体外共培养实验确立成骨细胞和骨细胞对MSC分化方向的影响，②通过条件性敲除小鼠模型探讨成骨分化晚期Cbfβ的缺陷对代谢和MAT的影响，③通过高通量筛选寻找Cbfβ调控的、决定MSC分化和MAT形成的细胞因子。本研究将为骨质疏松症和MAT形成提供新的理论基础和靶点。

Osteoporosis is an extremely common age-linked condition that is characterized by low bone mass and decreased bone strength. Marrow adipose tissue (MAT) is usually considered to be deleterious to bone health since 1) increased marrow adipocyte formation is at the expense of osteoblast differentiation since both originate from marrow mesenchymal stem cell (MSC); 2) Paracrine factors secreted by MAT promotes bone resorption and inhibits bone formation. Given the importance of MAT in bone metabolism, molecular mechanism underlying MAT formation is still unclear, and paracrine factors within skeletal microenvironment that regulate MAT is also largely unknown. Deletion of Cbfβ in pre-osteoblast reduces bone mass and increases MAT in mice, partially through paracrine signaling. Thus, to characterize how MSC differentiation fate and MAT formation are regulated by osteocyte/mature osteoblast-secreted cytokines, we would like to generate osteoblast and osteocyte-specific Cbfb conditional knockout mouse models. We proposed to ①determine the role of osteocyte and osteoblast in MSC differentiation using a co-culture system; ②to characterize the role of Cbfb in late stage of osteoblast differentiation regarding bone metabolism and MAT; ③to characterize Cbfβ-regulated mature osteoblast/osteocyte-secreted cytokines that play an important role in MSC differentiation fate determination and MAT formation. The proposed study will lead to new understanding in molecular mechanism underlying MAT formation. The proposed study will also lead to discovery of novel pharmaceutical targets for osteoporosis treatment.