Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1α

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1 alpha (TIF1 alpha), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1 alpha is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1 alpha resemble those seen in mice carrying an activating mutation of the calcium sensor receptor (Casr) gene and, in TIF1 alpha-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2, Cyp24a1, Trpv5, Trpv6, Calb1, S100g, Pthlh, and Spp1. Thus, our data indicate that TIF1 alpha represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1 alpha deficiency. Interestingly, the calcifying arteriopathy of TIF1 alpha-null mutant mice shares features with the human age-related Monckeberg's disease and, overall, the TIF1 alpha-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.