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.


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.
Li
Xianwu
X
University of Washington, Seattle, WA 98195, USA.
Speer
Mei Y
MY
Yang
Hsueh
H
Bergen
Jamie
J
Giachelli
Cecilia M
CM
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D002114:Calcinosis / Q000378:metabolism / Q000517:prevention & control*; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004872:Ergocalciferols / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects*; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D004872:Ergocalciferols; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium