Vitamin D receptor activators induce an anticalcific paracrine program in macrophages: requirement of osteopontin.

OBJECTIVE: Vascular calcification is highly correlated with morbidity and mortality, and it is often associated with inflammation. Vitamin D may regulate vascular calcification and has been associated with cardiovascular survival benefits.

METHODS AND RESULTS: We developed a macrophage/smooth muscle cell (SMC) coculture system and examined the effects of vitamin D receptor activators (VDRA), calcitriol and paricalcitol, on SMC matrix calcification. We found that treatment of SMC alone with VDRA had little effect on phosphate-induced SMC calcification in vitro. However, coculture with macrophages promoted SMC calcification, and this was strikingly inhibited by VDRA treatment. Several VDRA-induced genes, including bone morphogenetic protein-2 (BMP2), tumor necrosis factor-alpha, and osteopontin, were identified as candidate paracrine factors for the protective effect of VDRA. Of these, osteopontin was further investigated and found to contribute significantly to the inhibitory actions of VDRA on calcification in macrophage/SMC cocultures.

CONCLUSIONS: The ability of VDRA to direct a switch in the paracrine phenotype of macrophages from procalcific to anticalcific may contribute to their observed cardiovascular survival benefits.