Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential
Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential
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DOI：
10.1016/j.bone.2004.10.003
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发表时间：
2005-02-01
期刊：
影响因子：
4.1
通讯作者：
Nah, HD
中科院分区：
文献类型：
--
作者：
Fakhry, A;Ratisoontorn, C;Nah, HD
全身给予成纤维细胞生长因子（FGF）显示对动物骨形成的合成代谢作用，而体外细胞培养研究表明FGF阻断矿化骨结节形成。这些明显矛盾的结果表明，FGF作用的性质是复杂的，FGF的生物学效应可能取决于成骨细胞的分化阶段，与其他细胞因子的相互作用，或暴露于因子的时间和模式。因此，我们利用不同成熟阶段的原代颅骨骨细胞群来确定它们对骨中表达的因子2、FGF-9和BMP-2的反应。FGF-2和FGF-9刺激由更成熟的成骨细胞组成的细胞群的增殖，但不刺激具有未分化前体细胞的细胞群的增殖。FGF-2/-9的连续处理抑制了几种成骨细胞市场基因的表达和矿化。然而，用FGF-2/-9短暂预处理或用FGF-2/-9随后用BMP-2顺序处理导致矿化的显著刺激，表明FGF增强内在成骨潜力。此外，FGF-2和FGF-9增加了其他成骨因子BMP-2和TGF β-1的表达。同时，阻断内源性FGF信号，使用一个重要的转导的显性负性FGF受体（FgfR），导致BMP-2基因的表达大幅减少，首次证明内源性FGF/FgfR信号是一个积极的上游调控BMP-2基因在颅骨成骨细胞。相反，BMP拮抗剂头蛋白的表达被FGF-2和FGF-9抑制。因此，本研究的集体数据表明，FGF/FgfR信号通过选择性扩增定向成骨细胞群以及反向调节BMP-2和头蛋白基因表达来增强内在成骨潜力。(c)2004年爱思唯尔公司All rights reserved.
Systemically administered fibroblast growth factors (FGFs) show anabolic effects on bone formation in animals, whereas in vitro cell culture studies have demonstrated that FGFs block mineralized bone nodule formation. These apparently contradictory outcomes indicate that the nature of FGF action is complex and that the biological effect of FGFs may depend on the differentiation stage of osteoblasts, interaction with other cytokines, or the length and mode of exposure to factors. Thus, we have utilized primary calvarial bone cell populations at different maturation phases to determine their responses to 2, FGF-9, and BMP-2, the factors expressed in bone. FGF-2 and FGF-9 stimulated proliferation of the cell populations consisting of more mature osteoblasts, but not those with undifferentiated precursor cells. Continuous treatment with FGF-2/-9 inhibited expression of several osteoblast market genes and mineralization. However, brief pretreatment with FGF-2/-9 or sequential treatment with FGF-2/-9 followed by BMP-2 led to marked stimulation of mineralization, suggesting that FGFs enhance the intrinsic osteogenic potential. Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGF beta-1. Meanwhile, blocking endogenous FGF signaling, using a vitally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts. In contrast, expression of a BMP antagonist noggin was inhibited by FGF-2 and FGF-9. Thus, collective data from this study suggest that FGF/FgfR signaling enhances the intrinsic osteogenic potential by selectively expanding committed osteogenic cell populations as well as inversely regulating BMP-2 and noggin gene expression. (c) 2004 Elsevier Inc. All rights reserved.