如何调控骨髓间质干细胞（MSC）向成骨细胞分化，是代谢性骨病防治研究取得突破的关键之一。我们前期研究表明胰岛素受体底物1（IRS-1）能调节成骨细胞分化，IRS-1剔除小鼠出生时骨量减少而1年后骨量增加，该小鼠MSC中miR-503及其靶基因BMPR1a分别表达上调和下调，综合有关BMPR1a能促进MSC向成骨细胞分化但成骨细胞中BMPR1a条件性剔除小鼠却呈现骨量增加的报道，我们推测IRS-1可经miR-503介导的BMPR1a信号阶段特异性调节成骨细胞分化与功能。为此，我们先观察IRS-1剔除小鼠MSC中miR-503及BMPR1a的表达变化及与成骨标志物表达的相关性，通过相关基因剔除或过表达，确定IRS-1剔除小鼠后期的骨量增加是否由miR-503增加或BMPR1a下降引起；建立BMPR1a转基因且IRS-1剔除的小鼠，确认IRS-1可经BMPR1a调节成骨细胞功能及阶段特异性分化。

How to regulate the bone marrow mesenchymal stem cells (MSC) differentiate into osteoblast is one of the key points for the metabolic bone disease research. Our previously study showed that insulin receptor substrate 1 (IRS-1) can regulate the differentiation of osteoblasts, and found that IRS-1 knock-out mice decreased the bone mass when born but increased after one year, the expression of miR-503 was increased but it's target BMPR1a was decreased in MSC. After analyzed most of the studies about the function of BMPR1a, we supposed that IRS-1 would regulate the time-specific differentiation of MSC to osteoblast through BMPR1a mediated by miR-503. We will then observe the dynamic expression of miR-503,BMPR1a and bone metabolic markers in IRS-1 knock-out mice, evaluate the correlation between miR-503, BMPR1a and bone markers, and validate the time-dependent change of bone mass in IRS-1 out mice is due to the different roles of BMPR1a. BMPR1a transgene mice will be set up to observe the effect of BMPR1a on the MSC differentiation, IRS-1 will be knocked out in BMPR1a transgene mice by mated with IRS-1 knock-out mice, and through which we will showed that IRS-1 can regulate the time-dependent differentiation of MSC and the activity of osteoblast.