Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-α

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2012-05, Vol.27 (5), p.1800-1806
• Main Authors: AOSHIMA, Yumie, MIZOBUCHI, Masahide, OGATA, Hiroaki, KUMATA, Chiaki, NAKAZAWA, Ai, KONDO, Fumiko, ONO, Naoko, KOIWA, Fumihiko, KINUGASA, Eriko, AKIZAWA, Tadao
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Cells, Cultured; Dose-Response Relationship, Drug; Emergency and intensive care: renal failure. Dialysis management; Fundamental and applied biological sciences. Psychology; Humans; Intensive care medicine; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Osteogenesis - drug effects; Osteogenesis - physiology; Phosphates - pharmacology; Receptors, Calcitriol - drug effects; Receptors, Calcitriol - physiology; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vascular Calcification - metabolism; Vertebrates: urinary system; Vitamin D - analogs & derivatives
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfr758

Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D(3) analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α. Human VSMCs were treated with either vehicle, maxacalcitol (10(-9) to 10(-7) M), or calcitriol (10(-9) to 10(-7) M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed. Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol. Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification.