周期性张应力对人牙周膜成纤维细胞增殖与CTGF表达的影响及其调控机制初探
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摘要
目的：采用多通道细胞牵张应力加载系统对体外培养的人牙周膜成纤维细胞(human periodontal ligament fibroblasts, hPDLFs)施加不同时间利于细胞增殖的周期性张应力,观察周期性张应力对hPDLFs增殖及结缔组织生长因子(connective tissue growing factor, CTGF)表达的影响；通过检测添加JNK、 p38MAPK、PI3K信号通路特异性抑制剂后hPDLFs表达CTGF的变化,明确各通路是否在周期性张应力诱导hPDLFs表达CTGF过程中发挥作用。
方法：
1采用多通道细胞牵张应力加载系统,以hPDLFs为对象构建细胞体外培养-力学刺激模型。观察细胞形态特征,绘制生长曲线,为细胞力学加载实验准备实验细胞。
2加力组分别给予周期性张应力刺激1h、6h、12h、24h,加载的幅度10%(每一个循环包括3s-stretch/3s-relaxation)频率0.1Hz (6cycles/分),并以未加力组为实验对照组。应用CCK-8法(Cell Counting Kit-8)检测hPDLFs增殖的情况；应用ELISA法检测培养细胞分泌到上清液中的CTGF蛋白；应用荧光定量RT-PCR技术检测细胞CTGF mRNA的表达。
3对应用JNK信号通路特异性抑制剂SP600125、p38MAPK信号通路特异性抑制剂SB203580、PI3K信号通路特异性抑制剂LY294002预处理的细胞,分别加力1h、6h、12h、24h,与未加抑制剂的加力1h、6h、12h、24h的细胞作为对照组,检测CTGF的表达。
结果：
1体外培养获得了典型且稳定的hPDLFs,适用于对hPDLFs进行力学加载实验。
2加载周期性张应力组与对照组相比较,在周期性张应力加载1h hPDLFs开始增殖,6h hPDLFs增殖比较明显,12h hPDLFs增殖达高峰,24h hPDLFs增殖开始降低；加载周期性张应力组与对照组相比较,1h hPDLFs表达CTGF开始增强、6h表达明显增强,12h hPDLFs表达CTGF达最高峰值、24h hPDLFs表达CTGF开始下降。
3加入JNK信号通路特异性抑制剂后,hPDLFs表达CTGF出现下降；而加入p38MAPK信号通路和P13K信号通路的特异性抑制剂后CTGF表达未发生明显改变。
结论：
1加载幅度10%,频率0.1Hz的周期性张应力可以诱导hPDLFs增殖,hPDLFs并开始表达分泌CTGF。
2在一定时间范围内,周期性张应力引起CTGF mRNA和蛋白水平的表达呈时间依赖性升高；其后随着时间的延长,CTGF的表达则开始下降。
3周期性张应力通过JNK通路的介导促进了hPDLFs对CTGF的表达。
Objective:To observe the effect of cyclic tensile stress on cells proliferation and expression of CTGF in the hPDLFs by imposing cyclic tensile stress on hPDLFs in vitro at different times with multi-channel cell stretch stress loading system; To clarify the role of JNK, p38MAPK, PI3K pathway in the cyclic tensile stress induced expression of CTGF in hPDLFs by using specific inhibitors of JNK,p38and PI3K.
Methods:
1. An in vitro culture-tensile stimulate models of hPDLFs were established by using a multi-channel cell stretch stress loading system. Cell morphology was observed and the growth curve was drawn, to prepare the experiment cells for mechanical loading experiments.
2. The cells of stress application group were given stimulation of cyclic tensile stress for1h,6h,12h,24h. The loading extent was set for10%(each cycle included3s-stretch/3s-relaxation), with frequency of0.1Hz (6cycles/min). The control group was not given any stimulation as the same time. The cells proliferation was determined byCCK-8assay (Cell Counting Kit-8). The concentrations of CTGF in the culture supernatant were measured by commercially available enzyme linked immunosorent assay(ELISA) kits according to manufacturer's instructions. The expression of CTGF mRNA was detected by real-time RT-PCR.
3. The cells of stress application for12h were given SP600125, SB203580and LY294002, the specific inhibitors of JNK, p38MAPK, PI3K respectively at the beginning, the CTGF expression of which was compared with the groups of none inhibitors.
Results:
1. The hPDLFs proliferated typically and stably in vitro, and could be be given cyclic tensile stress.
2. Compared with the control group, hPDLFs of stress application groups began to proliferate at1h, and proliferated manifestly at6h, and proliferation reached the peak at12h, then proliferation decreased at24h. Similarly, the expression of CTGF began to increase at1h, and increased manifestly at6h, and reached the peak at12h, then decreased at24h.
3. The expression of CTGF reduced by using the specific inhibitors of JNK, while the specific inhibitors of p38MAPK, PI3K had not the same effect.
Conclusion:
1. Cyclic tensile stress with extent of10%and frequency of0.1Hz can induce hPDLFs proliferation and CTGF expression.
2. In a certain time, cyclic tensile stress can induce a time-dependent increase in CTGF mRNA and protein levels. Along with the extending of time, CTGF expression decreases.
3. Cyclic tensile stress-inducible expression of CTGF in hPDLFs is mediated by JNK pathway.
方法：
1采用多通道细胞牵张应力加载系统,以hPDLFs为对象构建细胞体外培养-力学刺激模型。观察细胞形态特征,绘制生长曲线,为细胞力学加载实验准备实验细胞。
2加力组分别给予周期性张应力刺激1h、6h、12h、24h,加载的幅度10%(每一个循环包括3s-stretch/3s-relaxation)频率0.1Hz (6cycles/分),并以未加力组为实验对照组。应用CCK-8法(Cell Counting Kit-8)检测hPDLFs增殖的情况；应用ELISA法检测培养细胞分泌到上清液中的CTGF蛋白；应用荧光定量RT-PCR技术检测细胞CTGF mRNA的表达。
3对应用JNK信号通路特异性抑制剂SP600125、p38MAPK信号通路特异性抑制剂SB203580、PI3K信号通路特异性抑制剂LY294002预处理的细胞,分别加力1h、6h、12h、24h,与未加抑制剂的加力1h、6h、12h、24h的细胞作为对照组,检测CTGF的表达。
结果：
1体外培养获得了典型且稳定的hPDLFs,适用于对hPDLFs进行力学加载实验。
2加载周期性张应力组与对照组相比较,在周期性张应力加载1h hPDLFs开始增殖,6h hPDLFs增殖比较明显,12h hPDLFs增殖达高峰,24h hPDLFs增殖开始降低；加载周期性张应力组与对照组相比较,1h hPDLFs表达CTGF开始增强、6h表达明显增强,12h hPDLFs表达CTGF达最高峰值、24h hPDLFs表达CTGF开始下降。
3加入JNK信号通路特异性抑制剂后,hPDLFs表达CTGF出现下降；而加入p38MAPK信号通路和P13K信号通路的特异性抑制剂后CTGF表达未发生明显改变。
结论：
1加载幅度10%,频率0.1Hz的周期性张应力可以诱导hPDLFs增殖,hPDLFs并开始表达分泌CTGF。
2在一定时间范围内,周期性张应力引起CTGF mRNA和蛋白水平的表达呈时间依赖性升高；其后随着时间的延长,CTGF的表达则开始下降。
3周期性张应力通过JNK通路的介导促进了hPDLFs对CTGF的表达。
Objective:To observe the effect of cyclic tensile stress on cells proliferation and expression of CTGF in the hPDLFs by imposing cyclic tensile stress on hPDLFs in vitro at different times with multi-channel cell stretch stress loading system; To clarify the role of JNK, p38MAPK, PI3K pathway in the cyclic tensile stress induced expression of CTGF in hPDLFs by using specific inhibitors of JNK,p38and PI3K.
Methods:
1. An in vitro culture-tensile stimulate models of hPDLFs were established by using a multi-channel cell stretch stress loading system. Cell morphology was observed and the growth curve was drawn, to prepare the experiment cells for mechanical loading experiments.
2. The cells of stress application group were given stimulation of cyclic tensile stress for1h,6h,12h,24h. The loading extent was set for10%(each cycle included3s-stretch/3s-relaxation), with frequency of0.1Hz (6cycles/min). The control group was not given any stimulation as the same time. The cells proliferation was determined byCCK-8assay (Cell Counting Kit-8). The concentrations of CTGF in the culture supernatant were measured by commercially available enzyme linked immunosorent assay(ELISA) kits according to manufacturer's instructions. The expression of CTGF mRNA was detected by real-time RT-PCR.
3. The cells of stress application for12h were given SP600125, SB203580and LY294002, the specific inhibitors of JNK, p38MAPK, PI3K respectively at the beginning, the CTGF expression of which was compared with the groups of none inhibitors.
Results:
1. The hPDLFs proliferated typically and stably in vitro, and could be be given cyclic tensile stress.
2. Compared with the control group, hPDLFs of stress application groups began to proliferate at1h, and proliferated manifestly at6h, and proliferation reached the peak at12h, then proliferation decreased at24h. Similarly, the expression of CTGF began to increase at1h, and increased manifestly at6h, and reached the peak at12h, then decreased at24h.
3. The expression of CTGF reduced by using the specific inhibitors of JNK, while the specific inhibitors of p38MAPK, PI3K had not the same effect.
Conclusion:
1. Cyclic tensile stress with extent of10%and frequency of0.1Hz can induce hPDLFs proliferation and CTGF expression.
2. In a certain time, cyclic tensile stress can induce a time-dependent increase in CTGF mRNA and protein levels. Along with the extending of time, CTGF expression decreases.
3. Cyclic tensile stress-inducible expression of CTGF in hPDLFs is mediated by JNK pathway.
引文
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