Maternal loss of Cyp24a1 causes increased intestinal calcium absorption and hypercalcemia during pregnancy but reduced skeletal resorption during lactation in mice

Maekawa, Alexandre S. (2025) Maternal loss of Cyp24a1 causes increased intestinal calcium absorption and hypercalcemia during pregnancy but reduced skeletal resorption during lactation in mice. Masters thesis, Memorial University of Newfoundland.

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Abstract

Inactivating mutations of 24-hydroxylase (CYP24A1) cause mild hypercalcemia in humans that can become severe during pregnancy. We studied Cyp24a1 null mice (NULL) during reproductive cycles, hypothesizing that they have a greater increase in calcitriol during pregnancy, leading to a greater increase in intestinal calcium absorption that causes hypercalcemia. We also hypothesized that bone loss would be reduced during lactation due to a persistent increase in intestinal calcium absorption. Wild-type (WT) and NULL females were mated with heterozygous (HET) males. We examined them at baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and during four weeks of post-weaning recovery (R1-4). Tests included intestinal calcium absorption, bone mineral content (BMC), μCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, hematocrit, milk analysis, and intestinal gene expression. At LP, both NULL and WT mice saw a ~12% increase in BMC. In NULLs, calcitriol was 2.5-fold higher, with a 3-fold increase in intestinal calcium absorption, and marked hypercalcemia. By LL, NULLs remained hypercalcemic compared to WT and had reduced lactational BMC loss in the lumbar spine (11% vs. 21%, p<0.02). In summary, Cyp24a1 ablation raises intestinal calcium absorption and causes hypercalcemia during pregnancy and lactation, with reduced lactational BMC loss. Treatment for women with gestational hypercalcemia due to Cyp24a1 mutations should target lowering calcitriol or intestinal calcium absorption, as increased bone resorption is not the underlying issue.

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