24- 羟基分解代谢的缺失会增加降钙三醇和成纤维细胞生长因子-23,并改变胎鼠的钙和磷代谢

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM
JBMR Plus Pub Date : 2024-01-29 DOI:10.1093/jbmrpl/ziae012
David Bennin, Sarah A Hartery, B. J. Kirby, Alexandre S Maekawa, René St-Arnaud, Christopher S Kovacs
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引用次数: 0

摘要

正常人类和啮齿类动物胎儿体内的降钙三醇循环水平较低,部分原因是 24- 羟化酶(CYP24A1)对降钙三醇和 25- 羟维生素 D 的 24- 羟化作用增加。CYP24A1 的失活突变会导致出生后降钙素三醇水平过高和人类的 1 型婴儿高钙血症,但 CYP24A1 的缺失是否会对胎儿造成干扰尚不清楚。我们假设,胎鼠体内 Cyp24a1 的缺失会导致高钙三醇、高钙血症和胎盘钙转运增加。Cyp24a1+/-小鼠与WT、Cyp24a1+/-和Cyp24a1无效胎儿交配妊娠。qPCR证实了Cyp24a1的缺失,以及S100g、Ncx1和Casr在无效胎盘中增加了2倍,但在胎儿肾脏中没有增加;这些变化预示着胎盘钙转运的增加。然而,胎盘 45Ca 和 32P 转运在无效胎儿中没有变化。不同基因型的胎儿灰分重量和矿物质含量、胎盘重量、冠臀长度和骨骼形态没有差异。无效胎儿的血清 P1NP 和骨骼中 Sost 和 Blgap 的表达量减少,而 Calcr 的表达量增加。总之,胎儿小鼠中 Cyp24a1 的缺失会导致高钙血症、轻度低磷血症、FGF23 增加,但不会改变骨骼发育。钙在骨骼中的结合减少可能是导致高钙血症的原因之一,但不会导致骨骼矿物质含量明显降低。研究结果预测,CYP24A1同源或复合杂合失活突变的人类胎儿也会在子宫内出现高钙血症,但骨骼发育正常。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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 CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. Cyp24a1+/- mice were mated to create pregnancies with WT, Cyp24a1+/- and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1+/- fetuses only), with 3.5-fold increased calcitriol, 4-fold increased FGF23, and unchanged PTH. qPCR confirmed absence of Cyp24a1 and 2-fold increases in S100g, Ncx1 and Casr in null placentas but not fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45Ca and 32P 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 P1NP and bone expression of Sost and Blgap were reduced while Calcr was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, 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 skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development.
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来源期刊
JBMR Plus
JBMR Plus Medicine-Orthopedics and Sports Medicine
CiteScore
5.80
自引率
2.60%
发文量
103
审稿时长
8 weeks
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