Development of endocrine pathways in the regulation of calcium homeostasis

The mammalian fetus is maintained hypercalcaemic relative to its mother by the action of a calcium pump believed to be located at the basement membranes of the epithelial cells of the fetal chorion. It has recently been demonstrated that the activity of this putative pump is stimulated by a new fetal hormone, parathyroid hormone-related protein, described originally as the product of a human BEN cell line which was derived from a lung tumour associated with hypercalcaemia of malignancy. Whereas the circulating level of immunoreactive parathyroid hormone in the fetus is very low, in keeping with the hypercalcaemia, the plasma concentrations of bioactive parathyroid hormone and parathyroid hormone-related protein can be measured using a sensitive cytochemical bioassay and the separate concentrations assessed by pre-incubation with appropriate antisera. The total plasma concentration of both hormones is inversely related to the prevailing calcium ion concentration but the set point of parathyroid hormone-related protein is probably higher than that for parathyroid hormone. Probably as a result of the hypercalcaemia, the circulating concentration of calcitonin is also higher than in maternal plasma and may serve to limit bone resorption to favour net bone accretion as part of the overall growth of the fetus. Vitamin D and its most active metabolite, 1,25(OH)2D, can pass across the placenta in either direction, in contrast to most peptide hormones. In addition to the supply of some 1,25(OH)2D by the mother to her fetus, the fetal placenta and fetal kidneys can all synthesize 1,25(OH)2D. The relative concentrations circulating in maternal and fetal plasma pools vary with the species, presumably as a result of differing importance of the three sources of supply to the fetus and the relative concentrations of vitamin D-binding protein circulating in mother and fetus. The importance of parathyroid hormone-related protein derived from fetal parathyroid glands has been clearly demonstrated in the fetal sheep. Such animals develop rickets following the removal of their parathyroid glands, despite the demonstration of this substance in fetal placental membranes. However, the relative importance of the parathyroid glands versus the placenta and its membranes as the principal source of parathyroid hormone-related protein remains to be elucidated and may vary with species.