骨髓间充质干细胞(BMSC)向成骨分化减少是老年性骨质疏松(SOP)发生的关键因素，但其调控机制未完全阐明。课题组前期通过全基因表达谱分析发现衰老模型小鼠BMSC中热休克因子4（HSF4）显著上调，且HSF4可抑制人和鼠BMSC成骨分化，促进其成脂分化；进一步利用基因表达谱筛选敲低HSF4的BMSC，发现其FGFR2明显上调，并提示HSF4可能通过抑制FGFR2等途径调控成骨/成脂分化关键转录因子表达，抑制BMSC成骨分化与促进SOP发生。本项目拟构建BMSC敲除HSF4基因的小鼠与细胞模型，在分子、细胞和整体水平进一步明确HSF4在SOP发生中的作用。阐明HSF4下调FGFR2的机制，以及HSF4与FGFR2上调成骨/下调成脂分化关键转录因子表达，进而抑制成骨分化、促进SOP发生的机制。并探讨靶向抑制HSF4对缓解SOP的作用，为骨代谢调节机制提出新观点，并为SOP防治提供新靶点。

The decrease of osteogenic differentiation of bone marrow mesenchymal stem cell(BMSC) is the key factor for the pathogenesis of senile osteoporosis(SOP), but the regulatory mechanism is not fully elucidated. In preliminary, the research group found that heat shock factor 4(HSF4) in BMSC of aging model mice was significantly up-regulated by whole Gene expression profiling analysis, and HSF4 could inhibit the osteogenic differentiation and promote the adipogenic differentiation of human and murine BMSC. Screening out the whole Gene expression profiling analysis of knock-down-HSF4 BMSC showed that the expression of FGFR2 was significantly increased, suggesting that HSF4 may regulate the expression of key transcription factors in osteogenic / adipogenic differentiation lead to inhibiting the osteogenic differentiation of BMSC and promoting SOP by inhibiting FGFR2. The aim of this project is to construct the models of mice and cells by knocking out HSF4 in BMSC, to further clarify the role of HSF4 in the pathogenesis of SOP at molecular, cellular and global levels. To elucidate the mechanism of HSF4 down-regulate FGFR2 ，and the mechanism of HSF4 and Fgfr2 up-regulating/down-regulating the expression of the key transcription factors of osteogenic differentiation/adipogenic differentiation, thus inhibiting the differentiation of osteogenic differentiation and promoting the pathogenesis of SOP. Exploring the role of targeted inhibition of HSF4 in alleviating SOP, and it will provide a new viewpoint for the regulated mechanism of bone metabolism and a new target for the prevention and treatment of SOP.