title: In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation.
abstract: 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/β-catenin signaling was evidenced by the translocation of β-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 β-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 β-catenin and the expression of its target genes. The role of Wnt/β-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/β-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/β-catenin signaling pathways.
authors.affiliation: Unidad de Investigacion, IMIBIC, Hospital Reina Sofía, Avda. Menéndez Pidal s/n, Córdoba, Spain.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Martínez-Moreno
authors.forename: Juan R
authors.initials: JR
authors.lastname: Muñoz-Castañeda
authors.forename: Carmen
authors.initials: C
authors.lastname: Herencia
authors.forename: Addy Montes de
authors.initials: AM
authors.lastname: Oca
authors.forename: Jose C
authors.initials: JC
authors.lastname: Estepa
authors.forename: Rocio
authors.initials: R
authors.lastname: Canalejo
authors.forename: Maria E
authors.initials: ME
authors.lastname: Rodríguez-Ortiz
authors.forename: Pablo
authors.initials: P
authors.lastname: Perez-Martinez
authors.forename: Escolástico
authors.initials: E
authors.lastname: Aguilera-Tejero
authors.forename: Antonio
authors.initials: A
authors.lastname: Canalejo
authors.forename: Mariano
authors.initials: M
authors.lastname: Rodríguez
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Almadén
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004872:Ergocalciferols / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010710:Phosphates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D061205:Vascular Calcification / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004872:Ergocalciferols; D010710:Phosphates; D051153:Wnt Proteins; D051176:beta Catenin; C084656:paricalcitol; D002117:Calcitriol