MECHANISMS OF FGF RESPONSES IN OSTEOGENIC CELLS

描述（由申请人提供）：成纤维细胞生长因子（FGFs）和同源受体家族在包括骨骼和骨骼发育在内的许多发育过程中起着重要作用。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，导致许多人骨形态发生疾病，包括侏儒症和颅缝早闭综合征。本项目的主要重点是研究成骨细胞对FGF的反应机制。虽然在大多数细胞类型中，FGFs诱导增殖并防止细胞凋亡，但成骨细胞表现出阶段特异性反应。未成熟的成骨细胞反应为增殖增加，而分化的成骨细胞则失去增殖反应并发生广泛的细胞凋亡。暴露于构成性FGF信号会抑制它们的分化能力。了解这些反应背后的机制将进一步加深我们对颅骨成骨细胞中过量FGF信号的病理影响的理解，包括颅缝闭合和颅骨畸形，以及FGF在成骨细胞生长和分化的生理控制中的作用。我们已经获得的结果表明，FGFs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，因此这一现象可能在FGF诱导的分化障碍中起重要作用。我们还观察到HMG结构域转录因子家族成员Sox2的显著诱导表达，并表明Sox2的组成性表达可以抑制成骨细胞分化并导致Wnt信号下调。本项目的目标是：1)进一步研究成骨细胞对FGF信号的生物学反应机制，探讨Sox2和Wnt信号在成骨细胞对FGF的反应中的作用，确定Sox2如何调节Wnt信号；2)研究FGF信号在成骨细胞中诱导Sox2表达的机制，这似乎是一种细胞类型特异性反应；3)利用fgf诱导的颅缝闭锁小鼠模型和成骨细胞谱系中Sox2表达受损的小鼠，在体内验证来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.