Mechanical stress induces Interleukin-11 expression to stimulate osteoblast differentiation
Mechanical stress induces Interleukin-11 expression to stimulate osteoblast differentiation
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DOI：
10.1016/j.bone.2009.07.087
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发表时间：
2009-12-01
期刊：
影响因子：
4.1
通讯作者：
Matsumoto, Toshio
中科院分区：
文献类型：
--
作者：
Kido, Shinsuke;Kuriwaka-Kido, Rika;Matsumoto, Toshio
机械应力诱导骨形成的分子机制尚不清楚。我们证明了机械卸载抑制和重新加载增强白细胞介素(IL)-11基因在小鼠后肢的体内表达。体外液体剪切应力（FSS）对成骨细胞的机械应力快速、短暂地促进fosB基因转录，刺激Delta fosB /JunD复合物与IL-11基因启动子激活蛋白(AP)-1位点结合，促进IL-11基因转录。抗IL-11抗体阻断机械应力诱导的成骨细胞生成增强和脂肪生成抑制，提示IL-11是机械应力刺激成骨细胞分化的必要条件。小干扰RNA （small interfering RNA, siRNA）下调Delta FosB/JtmD可抑制Delta FosB/JunD的过表达，增强IL-11基因启动子活性。与我们之前的观察一致，Delta FosB的上调依赖于环AMP反应元件结合蛋白（CREB）的激活，通过Ca2+依赖的细胞外信号调节激酶（ERK）的激活来磷酸化CREB，机械应力诱导的IL-11基因转录激活依赖于Ca2+-ERK途径。目前的研究结果还表明，FSS在体外增强成骨细胞的典型Wnt信号，机械卸载诱导和重新加载抑制典型Wnt信号抑制剂dickkopf2 （Dkk2）的体内表达。此外，IL-11 siRNA增强了FSS抑制的Dkk2表达，IL-11转基因小鼠成骨细胞的Dkk2 mRNA表达低于野生型小鼠。这些观察结果与机械应力通过增强OFosB/JunD与IL-11基因启动子的结合来刺激IL-11基因转录的观点一致，并且IL-11的增加至少在一定程度上通过减少Dkk2表达来增强典型Wnt信号，从而刺激成骨细胞分化。(C) 2009爱思唯尔公司版权所有。
Molecular mechanism of mechanical stress-induced bone formation remains unclear. We demonstrate that mechanical unloading suppresses and reloading enhances Interleukin (IL)-11 gene expression in the hindlimb of mice in vivo. Mechanical stress to osteoblasts by fluid shear stress (FSS) in vitro rapidly and transiently enhances fosB gene transcription, stimulates binding of Delta FosB/JunD complex to activator protein (AP)-1 site of the IL-11 gene promoter, and enhances IL-11 gene transcription. Anti-IL-11 antibody blocks mechanical stress-induced enhancement of osteoblastogenesis and suppression of adipogenesis, suggesting the requirement of IL-11 for the stimulation of osteoblast differentiation by mechanical stress. Downregulation of Delta FosB/JtmD by small interfering RNA (siRNA) suppresses and overexpression of Delta FosB/JunD enhances IL-11 gene promoter activity. Consistent with our previous observations that up-regulation of Delta FosB depends upon activation of cyclic AMP response element-binding protein (CREB) via Ca2+-dependent activation of extracellular signal-regulated kinase (ERK) to phosphorylate CREB, mechanical stress-induced activation of IL-11 gene transcription is dependent upon Ca2+-ERK pathway. Present results also demonstrated that FSS to osteoblasts enhances canonical Wnt signaling in vitro, and that mechanical unloading induces and reloading suppresses the expression of a canonical Wnt signal inhibitor, dickkopf2 (Dkk2), in vivo. In addition, IL-11 siRNA enhances Dkk2 expression suppressed by FSS, and osteoblasts from IL-11 transgenic mice show reduced Dkk2 mRNA expression than those from wild-type mice. These observations are consistent with the notion that mechanical stress stimulates IL-11 gene transcription via an enhanced OFosB/JunD binding to the IL-11 gene promoter, and that increased IL-11 enhances canonical Wnt signal at least in part via a reduction in Dkk2 expression to stimulate osteoblast differentiation. (C) 2009 Elsevier Inc. All rights reserved.