ROLE OF FGF SIGNALING IN BONE DEVELOPMENT

骨骼形态发生是由信号分子网络控制的，这些信号分子首先决定了间充质谱系中未分化干细胞的命运，然后调节成骨细胞的增殖和分化。在影响骨形态发生的信号分子中，成纤维细胞生长因子（FGF）及其同源受体（FGFR）最近被证明在软骨内和膜内骨形成中发挥重要作用。FGFR3的激活突变已被证明与几种遗传形式的人类侏儒症有关，FGFR1、FGFR2和FGFR3的其他激活突变与许多颅缝闭锁综合征有关。小鼠基因实验证实，不受调节的FGF信号导致骨畸形，并提示FGF可能作为骨生长的负调节因子。然而，FGFs影响成骨细胞（如软骨细胞和成骨细胞）增殖分化的分子机制仍有待阐明。本研究的目的是研究软骨细胞对FGF信号的反应。我们已经证明FGF治疗可以抑制软骨细胞的增殖，并且这种抑制需要激活STAT-1通路。通过对E15小鼠胚胎跖骨雏形的器官培养，我们也证明了FGFs调节软骨细胞增殖和骨骼发育，并且这种作用也需要STAT-1。我们希望了解软骨细胞对FGF信号的生长抑制反应的分子机制，以及FGF信号如何影响软骨细胞的增殖和分化。我们将研究1)软骨细胞中FGF受体激活的信号转导途径，重点研究STAT-1激活的机制，STAT-1在软骨细胞对FGF的反应中起重要作用；2)小鼠胚胎骨雏形器官培养过程中发生的分化过程如何受到FGF处理或FGF信号通路分子的影响；3)调节FGF信号对体内骨形态发生的影响，利用转基因和敲除小鼠，验证STAT-1如何影响长骨发育和软骨发育不良。

Skeletal morphogenesis is controlled by a network of signaling molecules that first determine the fate of undifferentiated stem cells of the mesenchymal lineage and then regulate the proliferation and differentiation of committed osteogenic cells. Among the signaling molecules which influence bone morphogenesis, fibroblast growth factors (FGF) and their cognate receptors (FGFR) have been recently shown to play a major role both in endochondral and intramembranous bone formation. Activating mutations in FGFR3 have been shown to be responsible for several genetic forms of human dwarfism, and other activating mutations in FGFR1, FGFR2 and FGFR3 have been linked to many craniosynostosis syndromes. Mouse genetic experiments have confirmed that unregulated FGF signaling causes bone malformations and suggested that FGFs may act as negative regulators of bone growth. However, the molecular mechanisms through which FGFs influence the proliferation of differentiation of osteogenic cells (e.g. chondrocytes and osteoblasts) remain to be elucidated. The goal of this research project is to study the response to FGF signaling of chondrocytes. We have shown that FGF treatment inhibits the proliferation of chondrocytes, and that this inhibition requires activation of the STAT-1 pathway. Using organ cultures of metatarsal bones rudiments of E15 murine embryos we have also shown that FGFs regulate chondrocyte proliferation and bone development and that this effect also requires STAT-1. We wish to understand the molecular mechanisms underlying the growth inhibitory response of chondrocytes to FGF signaling and how FGF signaling affects chondrocyte proliferation and differentiation. We will study 1) the signal transduction pathways activated by FGF receptors in chondrocytes with an emphasis on the mechanisms leading to activation on STAT-1, which plays an essential role in the chondrocyte response to FGF; 2) how the progress of the differentiation program which takes place during organ culture of bone rudiments from murine embryos is affected by FGF treatment or by molecules in the FGF signaling pathways; 3) the effect of modulating FGF signaling on bone morphogenesis in vivo, using transgenic and knockout mice, to verify how STAT-1 influences long bone development and chondrodysplasia.