Placental parathyroid hormone-related protein (PTHrP) regulates systemic mineral metabolism but not skeletal development in the fetus

Hartery, Sarah A. (2023) Placental parathyroid hormone-related protein (PTHrP) regulates systemic mineral metabolism but not skeletal development in the fetus. Masters thesis, Memorial University of Newfoundland.

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Abstract

Global deletion of Pthrp results in lethal chondrodysplasia, hypocalcemia, hyperphosphatemia, and reduced placental calcium transport. Conditional deletion of Pthrp from chondrocytes and osteoblasts have shown that locally produced PTHrP acts as a paracrine factor to control skeletal development. However, the source and role of PTHrP in fetal circulation are uncertain. We set out to determine if circulating fetal PTHrP derives from the placenta and controls systemic mineral concentrations and placental calcium transport. We used established models, Tpbpa/Ada-Cre mice and floxed Pthrp mice, to create a putative trophoblast-specific deletion of Pthrp (Tpbpa/Ada-Cre; Pthrpfl/fl). We mated Cre-Pthrpfl/+ females to Pthrpfl/fl males. Expected fetal genotypes are Pthrpfl/fl and Pthrpfl/+, with half of each expressing Cre. The four fetal genotypes appeared 1:1:1:1, indicating no prenatal losses. Cre-Pthrpfl/fl fetuses showed low serum calcium and higher serum phosphorus compared to their Pthrpfl/fl littermates and maternal values. Weights of placentas, intact fetuses, and fetal skeletal ash did not differ between the genotypes, nor did the fetal skeletal ash content of calcium, phosphorus, and magnesium. 5- micron longitudinal sections of fetal tibiae showed no change in length, morphology, or mineralization pattern by von Kossa staining. qPCR revealed increased placental expression of the gene for calbindin-D-9k (S100g), a gene involved in placental calcium transport. These findings suggest that placental PTHrP regulates systemic mineral levels in fetuses but has no direct role in skeletal development.

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