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Loss of 24-hydroxylated catabolism increases calcitriol and fibroblast growth factor 23 and alters calcium and phosphate metabolism in fetal mice
Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia...
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| Published in: | JBMR plus 2024-05, Vol.8 (5), p.ziae012-ziae012 |
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| Main Authors: | , , , , , |
| Format: | Article |
| Language: | English |
| Citations: | Items that this one cites |
| Online Access: | Get full text |
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| Summary: | Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of
cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of
in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The
mice were mated to create pregnancies with wildtype,
, and
null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to
fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of
and 2-fold increases in
, sodium-calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental
Ca and
P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and
were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of
in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of
will also be hypercalcemic in utero but with normal skeletal development. |
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| ISSN: | 2473-4039 2473-4039 |
| DOI: | 10.1093/jbmrpl/ziae012 |