Pregnancy challenges maternal calcium handling because sufficient calcium has to be transferred to the fetus to ensure fetal bone mass acquisition. 1,25(OH)2 vitamin D [1,25(OH)2D] is an important regulator of calcium homeostasis during adulthood, yet its role seems redundant for the maternal adaptations to pregnancy as well as during fetal development. However, not only deficiency but also excess of 1,25(OH)2D can be harmful and we therefore questioned whether high maternal 1,25(OH)2D levels may injure fetal development or neonatal outcome, as maternal-fetal transport of 1,25(OH)2D has been largely disputed. To this end, vitamin D receptor (VDR) null (Vdr(-/-)) females, displaying high 1,25(OH)2D levels, were mated with Vdr(+/-) males to obtain pregnancies with fetuses that are responsive (Vdr(+/-)) or resistant (Vdr(-/-)) to 1,25(OH)2D. Surprisingly, most of the Vdr(+/-) neonates died shortly after birth, whereas none of the Vdr(-/-). Mechanistically, we noticed that in Vdr(+/-) embryos, serum calcium levels were normal, but that skeletal calcium storage was reduced as evidenced by decreased mineralized bone mass as well as bone mineral content. More precisely, bone formation was decreased and the level of bone mineralization inhibitors was increased. This decreased fetal skeletal calcium storage may severely compromise calcium balance and survival at birth. In conclusion, these data indicate that high maternal 1,25(OH)2D levels are transferred across the placental barrier and adversely affect the total amount of calcium stored in fetal bones which is accompanied by neonatal death.
Keywords: 1,25(OH)(2) vitamin D; 1,25(OH)(2)D; ANK; BMD; Bone mineralization; Calcitonin-receptor; Calcium homeostasis; Calcr; Casr; DMP; DPD; E; ENPP; Embryonic development; FGF; HPRT; MGP; OPG; OPN; PHEX; PPi; PTH; PTH-related peptide; PTHrP; Pregnancy; RANKL; TNAP; TRAP; VDR; Vitamin D; bone mineral density; calcium-sensing receptor; dentin matrix protein; deoxypyridinoline; ectonucleotide pyrophosphatase phosphodiesterase; embryonic day; fibroblast growth factor; hypoxanthine–guanine phosphoribosyltransferase; matrix gla-protein; micro-computed tomography; osteopontin; osteoprotegerin; parathyroid hormone; phosphate-regulating gene with homologies to endopeptidases on the X chromosome; progressive ankylosis; pyrophosphates; receptor activator of nuclear factor NF-κβ-ligand; tartrate resistant acid phosphatase; tissue non-specific alkaline phosphatase; vitamin D receptor; μCT.
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