The prenylflavonoid Icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3 (STAT-3) regulation of C-X-C chemokine receptor type 4 (CXCR4) expression
The prenylflavonoid Icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3 (STAT-3) regulation of C-X-C chemokine receptor type 4 (CXCR4) expression
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DOI：
10.1016/j.bone.2017.08.028
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发表时间：
2017-12-01
期刊：
影响因子：
4.1
通讯作者：
Yong, E. L.
中科院分区：
文献类型：
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作者：
Lim, R. Z. L.;Li, L.;Yong, E. L.
在这项研究中，我们研究了天然异戊烯基黄酮淫羊藿苷（ICT）对人成骨细胞增殖和成骨功能的影响。我们观察到ICT剂量依赖性地增强成骨细胞增殖，在7天内增加了15%。这种细胞增殖的增加与成骨细胞功能的相应增加相关，如通过ALP分泌、细胞内钙离子内流和钙沉积所测量的。这些合成代谢作用与CXCR 4 mRNA和蛋白质表达增加4倍有关。使用小干扰RNA沉默CXCR 4蛋白表达逆转ICT诱导的细胞增殖、ALP活性和钙沉积增加。有趣的是，我们观察到Ia剂量依赖性地增加STAT-3磷酸化;并且这导致磷酸化STAT-3与CXCR 4基因的启动子区域的结合增加，以增加CXCR 4蛋白表达。此外，我们发现抑制STAT-3磷酸化导致CXCR 4蛋白表达减少;而使用组成型活性STAT-3载体增加STAT-3磷酸化显著增加CXCR 4水平。此外，STAT-3磷酸化的化学抑制取消了我们以前观察到的ICT诱导的成骨细胞增殖和功能的增加。最后，在雌激素缺乏的骨质疏松症大鼠模型中，ICT恢复了成骨细胞数量和CXCR 4表达。总之，细胞和动物模型都支持ICT的新发现;通过STAT-3的磷酸化，上调CXCR 4，以增加成骨细胞增殖和功能。(C)2017爱思唯尔公司All rights reserved.
In this study, we examined the effects of a natural prenylflavonoid Icaritin (ICT), on human osteoblast proliferation and osteogenic function. We observed that ICT dose-dependently enhanced osteoblast proliferation by similar to 15% over a 7 day period. This increase in cell proliferation was associated with corresponding increases in osteoblast functions as measured by ALP secretion, intracellular calcium ions influx and calcium deposition. These anabolic effects were associated with a 4-fold increase in CXCR4 mRNA and protein expression. Silencing of CXCR4 protein expression using small interfering RNA reversed ICT-induced increase in cell proliferation, ALP activity and calcium deposition. Interestingly, we observed that la dose-dependently increased STAT-3 phosphorylation; and this resulted in increased binding of phosphorylated STAT-3 to the promoter region of the CXCR4 gene, to increase CXCR4 protein expression. Furthermore, we found that inhibition of STAT-3 phosphorylation resulted in a decrease in CXCR4 protein expression; whilst increasing phosphorylation of STAT-3 using a constitutive active STAT-3 vector significantly increased CXCR4 levels. Moreover, the chemical inhibition of STAT-3 phosphorylation annulled our previously observed ICT-induced increases of osteoblast proliferation and function. Finally, in a rat model of estrogen-deficient osteoporosis, ICT restored both osteoblasts numbers and CXCR4 expression. Taken together, both cellular and animal models support the novel findings that ICT; through the phosphorylation of STAT-3, up-regulated CXCR4, to increase osteoblast proliferation and function. (C) 2017 Elsevier Inc. All rights reserved.