ROLE OF FGF SIGNALING IN BONE DEVELOPMENT

骨骼形态发生是由一系列信号分子控制的，这些信号分子首先决定间充质系未分化干细胞的命运，然后调节承诺的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(成纤维细胞生长因子)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人类侏儒症的遗传形式有关，而FGFR1、FGFR2和FGFR3的其他激活突变已被证明与许多颅缝融合综合征有关。小鼠遗传学实验证实，未调控的成纤维细胞生长因子信号转导导致骨畸形，并提示成纤维细胞生长因子可能是骨生长的负调控因子。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尚不清楚。本研究的目的是研究软骨细胞对成纤维细胞生长因子信号的反应。我们已经证明，成纤维细胞生长因子处理抑制软骨细胞的增殖，并且这种抑制需要激活STAT-1通路。利用E15小鼠胚胎的跖骨器官培养，我们还表明FGFs调节软骨细胞的增殖和骨的发育，这一作用也需要STAT-1。我们希望了解成纤维细胞生长抑制信号对软骨细胞生长抑制反应的分子机制，以及成纤维细胞生长因子信号如何影响软骨细胞的增殖和分化。我们将研究1)软骨细胞中由成纤维细胞生长因子受体激活的信号转导通路，重点研究在软骨细胞对成纤维细胞生长因子的反应中起重要作用的STAT-1的激活机制；2)成纤维细胞生长因子处理或成纤维细胞生长因子信号通路中的分子如何影响小鼠胚胎骨骼器官培养过程中发生的分化程序的进展；3)利用转基因和基因敲除小鼠，在体内调节成纤维细胞生长因子信号对骨形态发生的影响，以验证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.