Maternal loss of 24-hydroxylase causes increased intestinal calcium absorption and hypercalcemia during pregnancy but reduced skeletal resorption during lactation in mice

Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increa...

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Published in:Journal of bone and mineral research 2024-11, Vol.39 (12), p.1793
Main Authors: Maekawa, Alexandre S, Bennin, David, Hartery, Sarah A, Kirby, Beth J, Poulton, Ingrid J, St-Arnaud, René, Sims, Natalie A, Kovacs, Christopher S
Format: Article
Language:English
Subjects:
Animals
Bone Resorption - metabolism
Bone Resorption - pathology
Calcitriol - blood
Calcitriol - metabolism
Calcium - metabolism
Female
Fibroblast Growth Factor-23
Hypercalcemia - metabolism
Hypercalcemia - pathology
Intestinal Absorption
Lactation
Male
Mice
Mice, Knockout
Pregnancy
Vitamin D3 24-Hydroxylase - genetics
Vitamin D3 24-Hydroxylase - metabolism
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Summary:Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, BMC by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, p
ISSN:0884-0431
1523-4681
1523-4681
DOI:10.1093/jbmr/zjae166