BASIC FIBROBLAST GROWTH FACTOR EXPRESSION IN BONE CELLS

骨细胞中基本成纤维细胞生长因子的表达

基本信息

项目摘要

Basic fibroblast growth factor (FGF-2), a potent mitogen for osteoblasts and marrow stromal cells, is synthesized by bone cells. FGF-2 null mice have marked decreased trabecular bone volume, decreased bone nodule formation in marrow cultures and reduce osteoclast formation in response to a variety of agonists. We hypothesize that FGF-2 regulates osteoblast replication and differentiation and that disruption of the FGF-2 gene results in impaired bone formation. In addition, osteoclast formation is reduced due to either insufficient support cells (osteoblasts), or reduced production of factors important for osteoclastogenesis. Aim 1: To elucidate the role of endogenous FGF-2 in bone formation. We will compare mice with no FGF-2 gene (FGF-2-/-) with wild type (FGF-2+/+) mice. Dynamic histomorphometry and bone densitometry will be performed on mice of different ages to determine the rate that decreased trabecular bone volume in FGF-2(-/-) mice develops. We will examine osteoblast differentiation in bone marrow stromal cell cultures and calvarial cell cultures from FGF-2 (-/-) and FGF-2 (+/+). We will determine the effect of loss of FGF-2 on gene markers of differentiation of early and mature osteoblasts including, CBFA1, type 1 collagen, alkaline phosphatase and osteocalcin. We will examine the expression of genes which support osteoblast differentiation which may be downstream of FGF-2 including BMP2 and TGFbeta. We will compare bone formation in calvariae by measuring DNA, thymidine labeling and proline incorporation into collagen and noncollagen proteins. We will determine whether in vivo administration of FGF-2 reverses bone loss in FGF-2 (-/-) mice. Aim 2: To determine whether osteoclast formation and bone resorption are altered in FGF-2 null mice. We will compare the ability of agonists to induce osteoclast formation using bone marrow, as well as coculture models of primary calvarial enriched osteoblasts and spleen cells from FGF-2 (-/-) and FGF-2 (+/+) mice. We will measure osteoclast precursor numbers in these animals by the CFU-GM assay. We will examine the expression of genes that are critical for osteoclast formation including osteoprotegerin ligand (OPGL), osteoprotegerin (OPG), receptor activator of NFKB (RANK) and macrophage colony stimulating factor. We will examine the expression of genes which are important in bone turnover which may be downstream of FGF-2 including PGHS-2, IGF-I, collagenase. To assess bone resorption, we will measure 45Ca release from prelabeled calvariae in the unstimulated and stimulated state. Analysis of bone formation and resorption in FGF-2 null mice is relevant not only to understanding the physiologic and pathologic role of this growth factor in bone remodeling, but also to facilitate the development of therapeutic usage of FGF-2 in bone disorders such as osteoporosis.
碱性成纤维细胞生长因子(FGF-2)是成骨细胞和骨髓基质细胞的一种有效的丝裂原,由骨细胞合成。在多种激动剂的作用下,FGF-2缺失小鼠的骨小梁体积明显减少,骨髓培养中骨结节形成减少,破骨细胞形成减少。我们假设FGF-2调节成骨细胞的复制和分化,FGF-2基因的破坏导致骨形成受损。此外,由于支持细胞(成骨细胞)不足或破骨细胞生成重要因子的减少,破骨细胞的形成也会减少。目的1:阐明内源性FGF-2在骨形成中的作用。我们将比较无FGF-2基因(FGF-2-/-)小鼠与野生型(FGF-2+/+)小鼠。将对不同年龄的小鼠进行动态组织形态测定和骨密度测定,以确定FGF-2(-/-)小鼠小梁骨体积减少的发生速率。我们将检测骨髓基质细胞培养和颅细胞培养中FGF-2(-/-)和FGF-2(+/+)的成骨细胞分化。我们将确定FGF-2缺失对早期和成熟成骨细胞分化的基因标记的影响,包括CBFA1、1型胶原、碱性磷酸酶和骨钙素。我们将检测支持成骨细胞分化的基因的表达,这些基因可能位于FGF-2的下游,包括BMP2和tgf - β。我们将通过测量DNA、胸苷标记和脯氨酸并入胶原蛋白和非胶原蛋白来比较颅骨的骨形成。我们将确定体内给药FGF-2是否能逆转FGF-2(-/-)小鼠的骨质流失。目的2:确定FGF-2缺失小鼠的破骨细胞形成和骨吸收是否发生改变。我们将比较激动剂诱导骨髓破骨细胞形成的能力,以及来自FGF-2(-/-)和FGF-2(+/+)小鼠的原代颅骨富集成骨细胞和脾脏细胞的共培养模型。我们将通过CFU-GM试验测量这些动物的破骨细胞前体数量。我们将研究对破骨细胞形成至关重要的基因的表达,包括骨保护素配体(OPGL)、骨保护素(OPG)、NFKB受体激活因子(RANK)和巨噬细胞集落刺激因子。我们将检查在骨转换中重要的基因的表达,这些基因可能是FGF-2的下游,包括PGHS-2, igf - 1,胶原酶。为了评估骨吸收,我们将测量预标记颅骨在未刺激和刺激状态下的45Ca释放量。分析FGF-2缺失小鼠的骨形成和吸收不仅有助于了解该生长因子在骨重塑中的生理和病理作用,而且有助于开发FGF-2在骨质疏松症等骨疾病中的治疗应用。

项目成果

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Marja Marie Hurley其他文献

Marja Marie Hurley的其他文献

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{{ truncateString('Marja Marie Hurley', 18)}}的其他基金

Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice
FGF23 在镰状细胞病小鼠骨、肾、血液和串扰中的作用
  • 批准号:
    10437233
  • 财政年份:
    2022
  • 资助金额:
    $ 25.47万
  • 项目类别:
Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice
FGF23 在镰状细胞病小鼠骨、肾、血液和串扰中的作用
  • 批准号:
    10597099
  • 财政年份:
    2022
  • 资助金额:
    $ 25.47万
  • 项目类别:
FGF2 Isoforms in Bone and Phosphate Homeostasis
骨和磷酸盐稳态中的 FGF2 同工型
  • 批准号:
    10320412
  • 财政年份:
    2013
  • 资助金额:
    $ 25.47万
  • 项目类别:
FGF2 Isoforms in Bone and Phosphate Homeostasis
骨和磷酸盐稳态中的 FGF2 同工型
  • 批准号:
    10026143
  • 财政年份:
    2013
  • 资助金额:
    $ 25.47万
  • 项目类别:
FGF2 Isoforms in Bone and Phosphate Homeostasis
骨和磷酸盐稳态中的 FGF2 同工型
  • 批准号:
    8735135
  • 财政年份:
    2013
  • 资助金额:
    $ 25.47万
  • 项目类别:
FGF2 Isoforms in Bone and Phosphate Homeostasis
骨和磷酸盐稳态中的 FGF2 同工型
  • 批准号:
    8628923
  • 财政年份:
    2013
  • 资助金额:
    $ 25.47万
  • 项目类别:
The University of Connecticut BRIDGES Network
康涅狄格大学桥梁网络
  • 批准号:
    6828356
  • 财政年份:
    2004
  • 资助金额:
    $ 25.47万
  • 项目类别:
Action of Anabolic Factors on Bone Formation in Mice
合成代谢因子对小鼠骨形成的作用
  • 批准号:
    7189060
  • 财政年份:
    2004
  • 资助金额:
    $ 25.47万
  • 项目类别:
Action of Anabolic Factors on Bone Formation in Mice
合成代谢因子对小鼠骨形成的作用
  • 批准号:
    7528585
  • 财政年份:
    2004
  • 资助金额:
    $ 25.47万
  • 项目类别:
Action of Anabolic Factors on Bone Formation in Mice
合成代谢因子对小鼠骨形成的作用
  • 批准号:
    8278563
  • 财政年份:
    2004
  • 资助金额:
    $ 25.47万
  • 项目类别:

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