PDF(Pubmed)
Abstract：
Bone-fat balance is crucial to maintain bone homeostasis. As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal stem cells (BMSCs) are delicately balanced for their differentiation commitment. However, the exact mechanisms governing BMSC cell fate are unclear. In this study, we discovered that fibroblast growth factor 9 (Fgf9), a cytokine expressed in the bone marrow niche, controlled bone-fat balance by influencing the cell fate of BMSCs. Histomorphology and cytodifferentiation analysis showed that Fgf9 loss-of-function mutation (S99N) notably inhibited bone marrow adipose tissue (BMAT) formation and alleviated ovariectomy-induced bone loss and BMAT accumulation in adult mice. Furthermore, in vitro and in vivo investigations demonstrated that Fgf9 altered the differentiation potential of BMSCs, shifting from osteogenesis to adipogenesis at the early stages of cell commitment. Transcriptomic and gene expression analyses demonstrated that FGF9 upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. Mechanistic studies revealed that FGF9, through FGFR1, promoted adipogenic gene expression via PI3K/AKT/Hippo pathways and inhibited osteogenic gene expression via MAPK/ERK pathway. This study underscores the crucial role of Fgf9 as a cytokine regulating the bone-fat balance in adult bone, suggesting that FGF9 is a potentially therapeutic target in the treatment of osteoporosis.
摘要：
骨-脂肪平衡对于维持骨稳态至关重要。作为成骨细胞和脂肪细胞的常见祖细胞，骨髓间充质干细胞（BMSCs）的分化承诺是微妙的平衡。然而,控制BMSC细胞命运的确切机制尚不清楚.在这项研究中,我们发现成纤维细胞生长因子9（Fgf9），在骨髓小生境中表达的细胞因子，通过影响BMSCs的细胞命运来控制骨脂平衡。组织形态学和细胞分化分析表明，Fgf9功能丧失突变（S99N）显着抑制成年小鼠骨髓脂肪组织（BMAT）的形成并减轻卵巢切除术引起的骨丢失和BMAT积累。此外，体外和体内研究表明，Fgf9改变了BMSCs的分化潜能，在细胞定型的早期阶段从成骨转变为脂肪形成。转录组和基因表达分析表明，FGF9上调了成脂基因的表达，同时在mRNA和蛋白质水平上下调了成骨基因的表达。机制研究表明，FGF9通过FGFR1通过PI3K/AKT/Hippo途径促进成脂基因表达，并通过MAPK/ERK途径抑制成骨基因表达。这项研究强调了Fgf9作为调节成人骨骼中骨-脂肪平衡的细胞因子的关键作用。提示FGF9是治疗骨质疏松症的潜在治疗靶点。
