Mineral Homeostasis in Murine Fetuses Is Sensitive to Maternal Calcitriol but Not to Absence of Fetal Calcitriol

Vitamin D receptor (VDR) null fetuses have normal serum minerals, parathyroid hormone (PTH), skeletal morphology, and mineralization but increased serum calcitriol, placental calcium transport, and placental expression of Pthrp, Trpv6, and (as reported in this study) Pdia3. We examined Cyp27b1 null fetal mice, which do not make calcitriol, to determine if loss of calcitriol has the same consequences as loss of VDR. Cyp27b1 null and wild-type (WT) females were mated to Cyp27b1+/- males, which generated Cyp27b1 null and Cyp27b1+/- fetuses from Cyp27b1 null mothers, and Cyp27b1+/- and WT fetuses from WT mothers. Cyp27b1 null fetuses had undetectable calcitriol but normal serum calcium and phosphorus, PTH, fibroblast growth factor 23 (FGF23), skeletal mineral content, tibial lengths and morphology, placental calcium transport, and expression of Trpv6 and Pthrp; conversely, placental Pdia3 was downregulated. However, although Cyp27b1+/- and null fetuses of Cyp27b1 null mothers were indistinguishable, they had higher serum and amniotic fluid calcium, lower amniotic fluid phosphorus, lower FGF23, and higher 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D than in WT and Cyp27b1+/- fetuses of WT mothers. In summary, loss of fetal calcitriol did not alter mineral or bone homeostasis, but Cyp27b1 null mothers altered mineral homeostasis in their fetuses independent of fetal genotype. Cyp27b1 null fetuses differ from Vdr null fetuses, possibly through high levels of calcitriol acting on Pdia3 in Vdr nulls to upregulate placental calcium transport and expression of Trpv6 and Pthrp. In conclusion, maternal calcitriol influences fetal mineral metabolism, whereas loss of fetal calcitriol does not. © 2018 American Society for Bone and Mineral Research.