REGULATION OF BONE DEVELOPMENT BY FGF SIGNALING

描述（由申请方提供）：成纤维细胞生长因子（FGF）和同源受体（FGFR）家族在大量发育过程中发挥重要作用，包括骨骼发育。FGFR 1 -3中的激活突变通过影响软骨细胞和成骨细胞（负责骨形成的两种主要细胞类型）的增殖和分化而引起许多人骨形态发生障碍，包括侏儒症和颅缝早闭综合征。本研究的主要目的是探讨软骨细胞对FGF信号的反应机制，并确定决定软骨细胞对FGF信号反应的关键事件。阐明这些机制将有助于阐明FGF信号在骨发育中的生理和病理作用。我们以前的研究表明，增殖的软骨细胞对FGF的反应是生长抑制，这种抑制需要STAT 1的功能，无论是在体外还是在体内。FGF还诱导肥大分化的某些方面，包括凋亡。除了STAT 1，我们已经表明FGF介导的生长抑制也需要视网膜母细胞瘤蛋白p107和p130，并且p107去磷酸化是软骨细胞FGF反应的早期关键事件。我们最近还发现了STAT 3在软骨内骨化中的新作用。本课题的主要目的是：1）研究p107去磷酸化在软骨细胞FGF反应中的作用和机制，以及FGF是否特异性激活PP 2A磷酸酶，导致p107去磷酸化。2)进一步研究软骨细胞中的FGF信号传导，以了解STAT 1在FGF反应中的作用。我们将确定STAT 1是否通过转录或非转录机制调节对FGF的生长抑制反应，并鉴定FGF激活或下调表达需要STAT 1功能的基因。3)目的：探讨STATS在骨发育中的作用及软骨细胞对FGF的反应。我们已经发现，在软骨细胞中的STATS的条件性敲除减少增殖，并加速生长板中的分化和凋亡。我们将研究这种效应的机制以及STAT 1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.