REGULATION OF BONE DEVELOPMENT BY FGF SIGNALING

描述（由申请人提供）：成纤维细胞生长因子（FGFs）和同源受体（FGFR）家族在包括骨骼发育在内的许多发育过程中起着重要作用。FGFR1-3的激活突变通过影响软骨细胞和成骨细胞（两种主要的骨形成细胞类型）的增殖和分化，导致许多人骨形态发生疾病，包括侏儒症和颅缝闭锁综合征。本项目的主要重点是研究机制并确定决定软骨细胞对FGF信号反应的关键事件。阐明这些机制有助于揭示FGF信号在骨发育中的生理和病理作用。我们之前的研究表明，增殖的软骨细胞对FGF的反应是生长抑制，这种抑制需要STAT1的功能，在体外和体内都是如此。FGF还可诱导某些方面的肥厚分化，包括细胞凋亡。除了STAT1，我们已经证明FGF介导的生长抑制也需要视网膜母细胞瘤蛋白p107和p130， p107去磷酸化是软骨细胞FGF反应的早期关键事件。我们最近也发现了STAT3在软骨内成骨中的新作用。本项目的目的是：1)研究p107去磷酸化在软骨细胞FGF应答中的作用和机制，FGF是否特异性激活PP2A磷酸酶导致p107去磷酸化。2)进一步研究软骨细胞中FGF信号通路，了解STAT1在FGF应答中的作用。我们将确定STAT1是否通过转录或非转录机制调节FGF的生长抑制反应，并确定FGF激活或下调表达需要STAT1功能的基因。3)探讨STATS在骨发育中的作用及软骨细胞对FGF的反应。我们发现，有条件地敲除软骨细胞中的STATS可减少增殖，并加速生长板中的分化和凋亡。我们将研究这种作用的机制，以及STAT1和STATS在软骨细胞增殖和分化中发挥相反作用的假设。

DESCRIPTION (provided by applicant): The family of fibroblast growth factors (FGFs) and cognate receptors (FGFR) plays an important role in a large number of developmental processes, including sketal development. Activating mutations in FGFR1-3 cause a number of human bone morphogenetic disorders, including dwarfism and craniosynostosis syndromes, by affecting the proliferation and differentiation of chondrocytes and osteoblasts, the two major cell types responsible for bone formation. The main focus of this project is to investigate the mechanisms and identify the key events which detrmine the response of chondrocytes to FGF signaling. Elucidating these mechansims should shed light on the physiological and pathological role of FGF signaling in bone development. Our previous studies have shown that proliferating chondrocytes respond to FGF with growth- inhibition and that this inhibition requires STAT1 function, both in vitro and in vivo. FGF also induces some aspects of hypertrophic differentiation, including apoptosis. In addition to STAT1, we have shown that FGF- mediated growth inhibition also requires the retinoblastoma proteins p107 and p130, and that p107 dephosphorylation is an early critical event in the FGF response of choncrocytes. We have also recently uncovered a novel role for STAT3 in endochondral ossification. The goals of this project are: 1) To study the role and the mechanism of p107 dephosphorylation in the FGF response of chondrocytes, and whether a specific activation of the PP2A phosphatase by FGF is responsible for p107 dephosphorylation. 2) To study further FGF signaling in chondrocytes to understand the role that STAT1 plays in the FGF response. We will determine whether STAT1 regulates the growth-inhibitory response to FGF by a transcriptional or non- transcriptional mechanism and identify the genes whose activation or downregulation of expression by FGF requires STAT1 function. 3) To investigate the role of STATS in bone development and the response of chondrocytes to FGF. We have found that a conditional knockout of STATS in chondrocytes reduces proliferation, and accelerates differentiation and apoptosis in the growth plate. We will study the mechanisms of this effect and the hypothesis that STAT1 and STATS play opposite roles in chondrocyte proliferatin and differentiation.