ROLE OF FGF SIGNALING IN BONE DEVELOPMENT

FGF 信号传导在骨骼发育中的作用

• 批准号: 6500633
• 负责人: CLAUDIO BASILICO
• 金额: $ 1.08万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500633
• 关键词: JAK kinase; achondroplasia; biological signal transduction; bone development; cell differentiation; chondrocytes; embryo /fetus cell /tissue; enzyme activity; fibroblast growth factor; gene targeting; genetically modified animals; growth factor receptors; laboratory mouse; organ culture; transcription factor

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.

骨形态发生受信号分子网络控制，信号分子网络首先决定间充质谱系的未分化干细胞的命运，然后调节定向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）最近已被证明在软骨内和膜内骨形成中起主要作用。 FGFR 3中的激活突变已被证明是人类侏儒症的几种遗传形式的原因，并且FGFR 1、FGFR 2和FGFR 3中的其他激活突变已与许多颅缝早闭综合征相关。 小鼠遗传实验已经证实，不受调节的FGF信号传导导致骨畸形，并表明FGF可能作为骨生长的负调节剂。 然而，FGF影响成骨细胞（例如软骨细胞和成骨细胞）增殖和分化的分子机制仍有待阐明。 本研究项目的目的是研究软骨细胞对FGF信号的反应。 我们已经表明，FGF治疗抑制软骨细胞的增殖，这种抑制需要激活STAT-1途径。 使用E15小鼠胚胎的跖骨雏形的器官培养物，我们还表明FGF调节软骨细胞增殖和骨发育，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，重点是导致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）在来自小鼠胚胎的骨雏形的器官培养期间发生的分化程序的进展如何受到FGF处理或FGF信号转导途径中的分子的影响; 3）使用转基因和敲除小鼠，在体内调节FGF信号传导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。