Pregnancy in Mice Lacking the Vitamin D Receptor: Normal Maternal Skeletal Response, But Fetal Hypomineralization Rescued by Maternal Calcium Supplementation

Rummens, Katrien; Cromphaut, Sophie J. Van; Carmeliet, Geert; Herck, Erik Van; Bree, Rieta Van; Stockmans, Ingrid; Bouillon, Roger; Verhaeghe, Johan

doi:10.1203/01.pdr.0000081302.06915.d3

Cited by 38 publications

(30 citation statements)

References 34 publications

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“…In this new study, with proper related controls, there was no difference in serum calcium, phosphorus, or PTH of Vdr Leuϩ/Ϫ or Vdr Leu null fetuses from Vdr Leuϩ/Ϫ mothers compared with WT fetuses from WT mothers (376). The results contradict the earlier study from the same group because Vdr Leuϩ/Ϫ fetuses were normocalcemic in the new study (376) but hypercalcemic in the earlier study (574). These recent results are identical to those obtained with the Vdr Bos model as noted above, in which WT, Vdr Leuϩ/Ϫ , and Vdr Leu null fetuses each have normal serum calcium, phosphorus, and PTH.…”

Section: Vdrcontrasting

confidence: 85%

“…Of these four models, studies have been performed in Vdr Bos null and Vdr Leu fetuses. Inconsistent data have been obtained from the Vdr Leu model that expresses an aberrant but functional VDR (376,574), and these data contrast somewhat with data obtained from Vdr Bos null fetuses that lack VDRs (342,372).…”

Section: A Regulation Of Serum Mineralsmentioning

confidence: 81%

“…The progeny of those studies were compared with unrelated WT females mated to WT males. The authors observed the fetal plasma calcium to be paradoxically increased in Vdr Leuϩ/Ϫ fetuses compared with WT fetuses from unrelated mothers, but the serum calcium was normalized (reduced) in Vdr Leuϩ/Ϫ fetuses whose mothers had been placed on the calcium-phosphate-lactose-enriched "rescue diet" (574). The ionized calcium (the physiologically relevant fraction) was not measured, nor were the unrelated WT control mothers and their fetuses studied on the enriched diet.…”

Section: A Regulation Of Serum Mineralsmentioning

confidence: 99%

“…The three other models (Vdr Leu , Vdr Mun , and Vdr Tok ) each deleted the exon that encodes the first zinc finger of VDR, but a splice variant is secreted which has normal ligand binding ability but no DNA binding ability (175,376,574,704,755). Of these four models, studies have been performed in Vdr Bos null and Vdr Leu fetuses.…”

Section: A Regulation Of Serum Mineralsmentioning

confidence: 99%

“…Data from Vdr Leuϩ/Ϫ fetal mice are inconsistent between the two studies reported by the same group (376,574), but it is only their most recent study that provided data from Vdr Leu null fetuses (376). Some of the problems with the Vdr Leuϩ/Ϫ fetal data include the presence of a mutant VDR that may cause aberrant signaling, and use of unrelated control mice in the first study.…”

Section: If Vdrmentioning

confidence: 99%

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Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Kovacs

2014

Physiological Reviews

208

188

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Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of mineral supply for the fetus. Instead, the placenta meets the fetal need for mineral by actively transporting calcium, phosphorus, and magnesium from the maternal circulation. These minerals are maintained in the fetal circulation at higher concentrations than in the mother and normal adult, and such high levels appear necessary for the developing skeleton to accrete a normal amount of mineral by term. Parathyroid hormone (PTH) and calcitriol circulate at low concentrations in the fetal circulation. Fetal bone development and the regulation of serum minerals are critically dependent on PTH and PTH-related protein, but not vitamin D/calcitriol, fibroblast growth factor-23, calcitonin, or the sex steroids. After birth, the serum calcium falls and phosphorus rises before gradually reaching adult values over the subsequent 24 -48 h. The intestines are the main source of mineral for the neonate, while the kidneys reabsorb mineral, and bone turnover contributes mineral to the circulation. This switch in the regulation of mineral homeostasis is triggered by loss of the placenta and a postnatal fall in serum calcium, and is followed in sequence by a rise in PTH and then an increase in calcitriol. Intestinal calcium absorption is initially a passive process facilitated by lactose, but later becomes active and calcitriol-dependent. However, calcitriol's role can be bypassed by increasing the calcium content of the diet, or by parenteral administration of calcium.

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Section: Vdrcontrasting

confidence: 85%

Section: A Regulation Of Serum Mineralsmentioning

confidence: 81%

Section: A Regulation Of Serum Mineralsmentioning

confidence: 99%

Section: A Regulation Of Serum Mineralsmentioning

confidence: 99%

Section: If Vdrmentioning

confidence: 99%

See 3 more Smart Citations

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Kovacs

2014

Physiological Reviews

208

188

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Absence of Calcitriol Causes Increased Lactational Bone Loss and Lower Milk Calcium but Does Not Impair Post-lactation Bone Recovery in Cyp27b1 Null Mice

Gillies

Ryan

Tonkin

et al. 2017

Journal of Bone and Mineral Research

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We hypothesized that adaptation to calcium supply demands of pregnancy and lactation do not require calcitriol. Adult Cyp27b1 null mice lack calcitriol and have hypocalcemia, hypophosphatemia, and rickets. We studied wild-type (WT) and null sister pairs raised on a calcium-, phosphorus-, and lactose-enriched "rescue" diet that prevents hypocalcemia and rickets. Bone mineral content (BMC) increased >30% in pregnant nulls, declined 30% during lactation, and increased 30% by 4 weeks post-weaning. WT showed less marked changes. Micro-CT revealed loss of trabecular bone and recovery in both genotypes. In lactating nulls, femoral cortical thickness declined >30%, whereas endocortical perimeter increased; both recovered to baseline after weaning; there were no such changes in WT. Histomorphometry revealed a profound increase in osteoid surface and thickness in lactating nulls, which recovered after weaning. By three-point bend test, nulls had a >50% decline in ultimate load to failure that recovered after weaning. Although nulls showed bone loss during lactation, their milk calcium content was 30% lower compared with WT. Serum parathyroid hormone (PTH) was markedly elevated in nulls at baseline, reduced substantially in pregnancy, but increased again during lactation and remained high post-weaning. In summary, pregnant Cyp27b1 nulls gained BMC with reduced secondary hyperparathyroidism, implying increased intestinal calcium delivery. Lactating nulls lost more bone mass and strength than WT, accompanied by increased osteoid, reduced milk calcium, and worsened secondary hyperparathyroidism. This implies suboptimal intestinal calcium absorption. Post-weaning, bone mass and strength recovered to baseline, whereas BMC exceeded baseline by 40%. In conclusion, calcitriol-independent mechanisms regulate intestinal calcium absorption and trabecular bone metabolism during pregnancy and post-weaning but not during lactation; calcitriol may protect cortical bone during lactation.

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

Ryan

Alhani

Sellars

et al. 2018

Journal of Bone and Mineral Research

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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.

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Pregnancy in Mice Lacking the Vitamin D Receptor: Normal Maternal Skeletal Response, But Fetal Hypomineralization Rescued by Maternal Calcium Supplementation

Cited by 38 publications

References 34 publications

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Absence of Calcitriol Causes Increased Lactational Bone Loss and Lower Milk Calcium but Does Not Impair Post-lactation Bone Recovery in Cyp27b1 Null Mice

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

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