Transcriptional induction of FosB/ΔFosB gene by mechanical stress in osteoblasts
Transcriptional induction of FosB/ΔFosB gene by mechanical stress in osteoblasts
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DOI：
10.1074/jbc.m404096200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
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作者：
Inoue, D;Kido, S;Matsumoto, T
骨的机械应力在维持骨量和强度方面起着关键作用。然而，机械应力诱导骨形成的分子机制尚未完全了解。在本研究中，我们证明，FosB和它的剪接变体DeltaFosB，这是已知的增加骨量刺激骨形成在体内，是迅速诱导的机械负荷在小鼠后肢骨在体内和流体剪切应力（FSS）在小鼠颅骨成骨细胞在体外的mRNA和蛋白质水平。FSS对FosB/DeltaFosB基因表达的诱导依赖于钆敏感的Ca 2+内流和随后的ERK 1/2激活。用荧光素酶报告基因分析小鼠FosB/DeltaFosB基因上游调控区，发现FSS诱导的FosB/DeltaFosB发生在转录水平，并由-603至-327的短片段赋予。DNA沉淀分析和DNA诱饵实验表明，ERK依赖性激活CREB结合CRE/AP-1样元件（命名为“CRE 2”）的位置-413在很大程度上有助于FSS的转录效应。这些结果表明，DeltaFosB参与机械应力诱导的细胞内信号级联，激活成骨细胞的成骨程序。
Mechanical stress to bone plays a critical role in maintaining bone mass and strength. However, the molecular mechanism of mechanical stress-induced bone formation is not fully understood. In the present study, we demonstrate that FosB and its spliced variant DeltaFosB, which is known to increase bone mass by stimulating bone formation in vivo, is rapidly induced by mechanical loading in mouse hind limb bone in vivo and by fluid shear stress (FSS) in mouse calvarial osteoblasts in vitro both at the mRNA and protein levels. FSS induction of FosB/DeltaFosB gene expression was dependent on gadlinium-sensitive Ca2+ influx and subsequent activation of ERK1/2. Analysis of the mouse FosB/DeltaFosB gene upstream regulatory region with luciferase reporter gene assays revealed that the FosB/DeltaFosB induction by FSS occurred at the transcriptional level and was conferred by a short fragment from -603 to -327. DNA precipitation assays and DNA decoy experiments indicated that ERK-dependent activation of CREB binding to a CRE/AP-1 like element (designated "CRE2") at the position of -413 largely contributed to the transcriptional effects of FSS. These results suggest that DeltaFosB participates in mechanical stress-induced intracellular signaling cascades that activate the osteogenic program in osteoblasts.