In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation
In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation
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DOI：
10.1152/ajprenal.00684.2011
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
Almaden, Yolanda
中科院分区：
文献类型：
--
作者：
Martinez-Moreno, Julio M.;Munoz-Castaneda, Juan R.;Almaden, Yolanda
Martinez-Moreno JM，Munoz-Castaneda Jr，Herencia C，Montes de Oca A，Estepa JC，Canalejo R，Rodriguez-Ortiz ME，Perez-Martinez P，Aguera-Tejero E，Canalejo A，Rodriguez M，Almaden Y。AM J Physiol Renal Physiol 303：F1136-F1144,2012。2012年8月8日首次出版；DOI：10.1152/ajprenal.00684.2011。-本研究探讨了两种维生素D受体激动剂骨化三醇和骨化醇对体外培养的人主动脉平滑肌细胞钙化的不同影响。人血管平滑肌细胞在高磷(HP)单独或添加骨化三醇10(-8)M(HP+CTR)或骨化三醇3.10(-8)M(HP+PC)的培养液中培养。HP诱导的钙化与骨形态发生蛋白2(BMP2)、Runx2/Cbfa1、MSX2和骨钙素等成骨因子的mRNA表达上调有关。在这些细胞中，Wnt/β-catenin信号被激活的证据是：β-catenin移位到细胞核内，以及直接靶基因Cyclin D1、Axin 2和Vcan/verscan的表达增加。在HP培养液中加入骨化三醇(HP+CTR)进一步增加钙化，并增强成骨因子的表达，同时显著提高核β-连环素水平和细胞周期蛋白D1、轴蛋白2和VCAN的表达。相反，加入骨钙素(HP+PC)不仅减少了钙化，而且下调了BMP2和其他成骨细胞表型标志物的表达，并下调了核β-连环素及其靶基因的表达。加入Wnt/β-catenin信号通路的特异性天然拮抗剂Dickkopf相关蛋白1(DKK-1)后，进一步证明了Wnt/β-catenin在磷酸和骨化三醇诱导的钙化中的作用。总之，骨化三醇和骨化醇对血管钙化的不同作用似乎是通过对BMP和Wnt/β-catenin信号通路的不同调节来实现的。
Martinez-Moreno JM, Munoz-Castaneda JR, Herencia C, Montes de Oca A, Estepa JC, Canalejo R, Rodriguez-Ortiz ME, Perez-Martinez P, Aguilera-Tejero E, Canalejo A, Rodriguez M, Almaden Y. In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/beta-catenin activation. Am J Physiol Renal Physiol 303: F1136-F1144, 2012. First published August 8, 2012; doi:10.1152/ajprenal.00684.2011.-The present study investigates the differential effect of two vitamin D receptor agonists, calcitriol and paricalcitol, on human aortic smooth muscle cells calcification in vitro. Human vascular smooth muscle cells were incubated in a high phosphate (HP) medium alone or supplemented with either calcitriol 10(-8)M (HP + CTR) or paricalcitol 3.10(-8) M (HP + PC). HP medium induced calcification, which was associated with the upregulation of mRNA expression of osteogenic factors such as bone morphogenetic protein 2 (BMP2), Runx2/Cbfa1, Msx2, and osteocalcin. In these cells, activation of Wnt/beta-catenin signaling was evidenced by the translocation of beta-catenin into the nucleus and the increase in the expression of direct target genes as cyclin D1, axin 2, and VCAN/versican. Addition of calcitriol to HP medium (HP + CTR) further increased calcification and also enhanced the expression of osteogenic factors together with a significant elevation of nuclear beta-catenin levels and the expression of cyclin D1, axin 2, and VCAN. By contrast, the addition of paricalcitol (HP + PC) not only reduced calcification but also downregulated the expression of BMP2 and other osteoblastic phenotype markers as well as the levels of nuclear beta-catenin and the expression of its target genes. The role of Wnt/beta-catenin on phosphate- and calcitriol-induced calcification was further demonstrated by the inhibition of calcification after addition of Dickkopf-related protein 1 (DKK-1), a specific natural antagonist of the Wnt/beta-catenin signaling pathway. In conclusion, the differential effect of calcitriol and paricalcitol on vascular calcification appears to be mediated by a distinct regulation of the BMP and Wnt/beta-catenin signaling pathways.