Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells
Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells
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DOI：
10.1016/j.atherosclerosis.2016.08.010
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发表时间：
2016-10-01
期刊：
影响因子：
5.3
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Nakahara, Takehiro;Kawai-Kowase, Keiko;Kurabayashi, Masahiko
背景和目的：成纤维细胞生长因子23 （FGF23）水平升高与慢性肾病患者心血管死亡率相关。然而，关于FGF23在血管钙化中的病理生理作用，临床和基础研究都显示了相互矛盾的证据。本研究的目的是确定FGF23在血管平滑肌细胞（SMCs）成骨基因表达中的作用。方法和结果：我们用表达人FGF23的腺病毒（Ad-FGF23）转染表达klotho和FGF受体的人主动脉SMCs （HASMCs）。我们观察到成骨细胞标记基因BMP2、BMP4、MSX2、RUNX2和ALP的表达显著降低，钙化减少。值得注意的是，Ad-FGF23增加了骨保护素（OPG） mRNA和蛋白水平，并且FGF23激活了人OPG启动子。此外，在过表达klotho的HASMCs中，FGF23上调了OPG的表达，而通过siRNA去除klotho则减弱了FGF23诱导的OPG表达。此外，在连续73例2型糖尿病患者接受心脏计算机断层扫描以确定冠状动脉钙评分（CCSs）时，血清FGF23水平与独立于磷酸盐的OPG和估计的肾小球滤过率（eGFR, r - 0.65, p < 0.01）呈正相关。与低CCSs患者（< 100）相比，高CCSs患者（>= 100）血清FGF23水平显著升高。结论：体外实验结果表明，FGF23可抑制HASMCs成骨细胞基因表达，诱导OPG表达。结合我们的横断面临床评估，本研究支持我们的假设，即FGF23抵消血管SMCs的成骨转化，作为缓解血管钙化的代偿机制的一部分。2016爱思唯尔爱尔兰有限公司版权所有。
Background and aims: Elevated fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular mortality in patients with chronic kidney disease. However, both clinical and basic research have demonstrated conflicting evidence regarding the pathophysiological role of FGF23 in vascular calcification. The aim of this study was to determine the role of FGF23 in the osteoblastic gene expression in vascular smooth muscle cells (SMCs).Methods and results: We transduce human aortic SMCs (HASMCs) expressing klotho and FGF receptors with the adenovirus expressing human FGF23 (Ad-FGF23). We observed significant decreases in the expression of osteoblast-marker genes including BMP2, BMP4, MSX2, RUNX2 and ALP, as well as reduced calcification. Notably, Ad-FGF23 increased mRNA and protein levels of osteoprotegerin (OPG), and human OPG promoter was activated by FGF23. Moreover, in HASMCs overexpressing klotho, FGF23 upregulated OPG expression, whereas depletion of klotho by siRNA attenuated FGF23-induced OPG expression. Furthermore, in 73 consecutive patients with type 2 diabetes mellitus undergoing cardiac computed tomography to determine coronary calcium scores (CCSs), serum FGF23 levels were positively correlated with OPG independent of phosphate and estimated glomerular filtration rate (eGFR, r - 0.65, p < 0.01). Serum FGF23 levels were significantly elevated in patients with high CCSs (>= 100) compared to those with low CCSs (< 100).Conclusions: Our in vitro results indicate that FGF23 suppresses osteoblastic gene expression and induces OPG expression in HASMCs. Together with our cross-sectional clinical assessment, the present study lends support to our hypothesis that FGF23 counteracts osteogenic conversion of vascular SMCs as a part of a compensatory mechanism to mitigate vascular calcification. (C) 2016 Elsevier Ireland Ltd. All rights reserved.