MECHANISMS OF FGF RESPONSES IN OSTEOGENIC CELLS

描述（由申请方提供）：成纤维细胞生长因子（FGF）家族和同源受体在大量发育过程中发挥重要作用，包括骨和骨骼发育。FGF受体（FGFR）的激活突变通过影响负责骨形成的两种主要细胞类型（软骨细胞和成骨细胞）的增殖和分化而引起许多人骨形态发生病症，包括侏儒症和颅缝早闭（颅缝过早闭合）综合征。该项目的主要重点是研究成骨细胞对FGF反应的机制。虽然在大多数细胞类型中，FGF诱导增殖并防止凋亡，但成骨细胞显示出阶段特异性反应。未成熟的成骨细胞以增加的增殖反应，而分化的成骨细胞反而失去增殖反应并经历广泛的凋亡。暴露于组成型FGF信号传导抑制其分化能力。了解这些反应的机制将进一步我们了解的病理影响，过多的FGF信号在颅骨成骨细胞，包括颅缝早闭和颅骨畸形，以及成骨细胞的生长和分化的生理控制中的FGF的作用。我们已经获得的结果表明FGF对成骨细胞的主要作用之一是抑制Wnt信号通路。Wnt信号是成骨细胞分化和功能所必需的，因此这种现象可能在FGF诱导的分化障碍中发挥重要作用。我们还观察到一个显着的诱导表达的Sox 2，HMG结构域家族的转录因子的成员，并表明，组成型表达的Sox 2可以抑制成骨细胞分化，并导致Wnt信号下调。本课题的主要目的是：1）进一步研究成骨细胞对FGF信号的生物学反应机制，探讨Sox 2和Wnt信号在成骨细胞对FGF反应中的作用，以及Sox 2如何调节Wnt信号：2）探讨FGF信号诱导成骨细胞表达Sox 2的机制，即Sox 2是一种细胞类型特异性反应; 3）使用FGF诱导的颅缝早闭的鼠模型和成骨细胞谱系中Sox 2表达受损的小鼠，在体内验证源自体外研究的观察结果和假设。

DESCRIPTION (provided by applicant): The family of fibroblast growth factors (FGFs) and cognate receptors plays an important role in a large number of developmental processes, including bone and skeletal development. Activating mutations in FGF receptors (FGFRs) cause a number of human bone morphogenetic disorders, including dwarfism and craniosynostosis (premature closure of cranial sutures) syndromes, by affecting the proliferation and differentiation of the two major cell types responsible for bone formation, chondrocytes and osteoblasts. The main focus of this project is the investigation of the mechanisms that determine the response to FGF of osteoblasts. While in most cell types FGFs induce proliferation and protect from apoptosis, osteoblasts display a stage-specific response. Immature osteoblasts respond with increased proliferation, while differentiating osteoblasts instead lose the proliferative response and undergo extensive apoptosis. Exposure to constitutive FGF signaling inhibits their ability to differentiate. Understanding the mechanisms underlying these responses will further our understanding of the pathological effects of excessive FGF signaling in calvarial osteoblasts, including craniosynostosis and skull malformations, as well as the role of FGFs in the physiological control of osteoblast growth and differentiation. We have obtained results indicating one of the major effects of FGFs on osteoblasts is inhibition of the Wnt signaling pathway. Wnt signaling is required for osteoblast differentiation and function, and thus this phenomenon could play an important role in the impairment of differentiation induced by FGF. We have also observed a striking induction of the expression of Sox2, a member of the HMG domain family of transcription factors, and shown that constitutive expression of Sox2 can inhibit osteoblast differentiation and cause Wnt signaling downregulation. The goals of this project are: 1) to further study the mechanisms which determine the biological response of osteoblasts to FGF signaling, investigate the role that Sox2 and Wnt signaling play in the response of osteoblasts to FGF, and determine how Sox2 modulates Wnt signaling; 2) to investigate the mechanisms by which FGF signaling induces Sox2 expression in osteoblasts, that appears to be a cell type-specific response; 3) verify in vivo the observations and hypotheses derived from in vitro studies using a murine model of FGF-induced craniosynostosis and mice with impaired Sox2 expression in the osteoblastic lineage.