近年来，骨髓间充质干细胞（BMSCs）向成骨细胞抑或脂肪细胞的分化失衡已然成为骨质疏松症研究领域的热点之一。我们前期研究发现成纤维细胞生长因子9（FGF9）功能缺失性点突变（S99N）纯合子小鼠关节发育障碍并意外发现成年杂合子小鼠骨密度显著升高，膜内成骨速率加快，成骨活性增强。体外研究显示BMSCs在成骨/成脂分化诱导条件下，FGF9显著抑制向成骨细胞的分化过程，但对成脂分化具有显著促进作用，提示FGF9可能对BMSCs成骨/成脂分化平衡具有重要调控作用。据此，本项目将利用FGF9细胞过表达、敲低及功能缺失突变和条件性过表达小鼠模型，研究FGF9对BMSCs成骨/成脂分化平衡和骨代谢的调控作用。利用RNA-seq、磷酸化芯片和通路抑制剂等手段阐明FGF9调控BMSCs分化的分子机制。预期结果将对认识FGF9基因功能、理解骨代谢疾病发病机制和开发新型诊断、治疗手段具有重要理论和应用价值。

In recent years, the imbalance of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts or adipocytes has become one of the hotspots in the field of osteoporosis. Our previous studies have found that fibroblast growth factor 9 (FGF9) loss of function point mutation (S99N) homozygous mouse showed joint developmental disorder and, unexpectedly, found adult heterozygous mice have significantly increased bone density, accelerated intramembranous osteogenesis rate and increased osteogenesis activity. In vitro osteogenic/adipogenic differentiation studies showed that FGF9 can significantly inhibit the differentiation of BMSCs into osteoblasts and promote differentiation into adipocytes, suggesting that FGF9 may be important for the regulation of osteogenic/adipogenic differentiation of BMSCs. Based on this, the project will use FGF9 overexpression, knockdown in cells and loss of function mutations and conditional overexpression mouse model to study the regulation of FGF9 on BMSCs osteogenesis/adipogenic differentiation and bone metabolism. The molecular mechanism of FGF9 regulating BMSCs differentiation was elucidated by means of RNA-seq, phosphorylation microarray and pathway inhibitor. The expected results will have important theoretical and practical value for understanding the function of FGF9 gene, understanding the pathogenesis of bone metabolic diseases and developing new diagnostic and therapeutic methods.