Alendronate inhibits VEGF expression in growth plate chondrocytes by acting on the mevalonate pathway.
Alendronate inhibits VEGF expression in growth plate chondrocytes by acting on the mevalonate pathway.
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DOI：
10.2174/1874325000903010083
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发表时间：
2009-10-01
期刊：
影响因子：
--
通讯作者：
Oberbauer AM
中科院分区：
文献类型：
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作者：
Evans KD;Oberbauer AM
双膦酸盐降低生长板处的软骨细胞周转并影响骨生长。同样，血管内皮生长因子（VEGF）通过影响生长板上的软骨细胞更新，在软骨内骨延长中发挥重要作用。为了研究双膦酸盐对生长板的作用是否通过VEGF起作用，评估了从生长小鼠分离并用临床使用的双膦酸盐阿仑膦酸盐处理的软骨内软骨细胞中VEGF蛋白表达和同种型转录。10μM和100μM浓度的阿仑膦酸钠降低分泌的VEGF蛋白表达，但不降低细胞相关蛋白。已知双膦酸盐抑制VEGF使用的甲羟戊酸细胞内信号传导途径。添加甲羟戊酸途径中间体法尼醇（FOH）和香叶基香叶醇（GGOH）与低浓度的阿仑膦酸钠相互作用，进一步减少分泌的VEGF蛋白，而FOH与高浓度的阿仑膦酸钠结合时，部分恢复VEGF蛋白的分泌。与蛋白质数据相似，添加阿仑膦酸钠降低了VEGF mRNA亚型。在低剂量阿仑膦酸钠时，GGOH甲羟戊酸途径中间体挽救了VEGF mRNA水平，而在高剂量阿仑膦酸钠时，两种中间体均未持续恢复VEGF mRNA水平。因此，双膦酸阿仑膦酸盐通过抑制甲羟戊酸途径下调VEGF mRNA和蛋白质的分泌形式来损害生长板软骨细胞更新。
Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosphonate on the growth plate works through VEGF, VEGF protein expression and isoform transcription in endochondral chondrocytes isolated from growing mice and treated with a clinically used bisphosphonate, alendronate, were assessed. Alendronate at 10µM and 100µM concentrations decreased secreted VEGF protein expression but not cell associated protein. Bisphosphonates are known to inhibit the mevalonate intracellular signaling pathway used by VEGF. Addition of the mevalonate pathway intermediates farnesol (FOH) and geranylgeraniol (GGOH) interacted with the low concentration of alendronate to further decrease secreted VEGF protein whereas FOH partially restored VEGF protein secretion when combined with the high alendronate. Similar to the protein data, the addition of alendronate decreased VEGF mRNA isoforms. VEGF mRNA levels were rescued by the GGOH mevalonate pathway intermediate at the low alendronate dose whereas neither intermediate consistently restored the VEGF mRNA levels at the high alendronate dose. Thus, the bisphophonate alendronate impairs growth plate chondrocyte turnover by down-regulating the secreted forms of VEGF mRNA and protein by inhibiting the mevalonate pathway.