Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy

Abstract

Parathyroid hormone (PTH)-like bioactivity, assayed as adenylate cyclase response in UMR 106-01 osteogenic sarcoma cells, was present in extracts of sheep fetal and maternal parathyroid glands and placenta. Preincubation of extracts with PTH(1-34) antiserum inhibited approximately 40% of the bioactivity in fetal parathyroid extracts, 50% in maternal parathyroid extracts, but only 10% of the bioactivity in the placental extract. Partial purification of placental extracts by chromatography yielded fractions containing PTH-like bioactivity which were similar in behaviour to that of PTH-related protein (PTHrP) from a human lung cancer cell line (BEN). An antiserum against synthetic PTHrP(1-16) partially inhibited the bioactivity of the placental extract and synthetic PTHrP(1-34), but had no effect on the bioactivity of bovine PTH(1-34) or bovine PTH(1-84). The placental PTH-like bioactivity was higher in mid- than in late gestation. Fetal parathyroid glands contained the highest PTH-like bioactivity. Thyroparathyroidectomy of one fetal twin lamb in each of 16 ewes between 110 and 125 days of gestation resulted in decreases of the plasma calcium concentration and reversal of the placental calcium gradient that existed between the ewe and the intact fetus. Perfusion of the placenta of each twin in anaesthetized ewes was carried out sequentially with autologous fetal blood in the absence of the exsanguinated fetus. The plasma calcium concentration in the blood perfusing the placenta of each twin increased, but reached a plateau at a lower concentration in the perfusing blood of thyroparathyroidectomized fetuses than in that of the intact fetuses. Addition of extracts of fetal parathyroid glands or of partially purified PTHrP resulted in further increases in plasma calcium in the autologous blood perfusing the placentae of thyroparathyroidectomized fetuses, but addition of bovine PTH(1-84) or rat PTH(1-34) had no effect. The presence of this PTH-like protein in the fetal parathyroid gland and placenta may contribute to the relative hypercalcaemia of the fetal lamb. This protein, which is similar to PTHrP associated with humoral hypercalcaemia of malignancy, stimulates the placental calcium pump responsible for maintaining a relative fetal hypercalcaemia during gestation.

Immunochemical Detection of Parathyroid Hormone-Related Protein in the Saccus Vasculosus of a Teleost Fish

“…In fetal sheep PTHrP is responsible, at least in part, for maintaining the differential gradient between high fetal serum calcium and that of the maternal circulation (Rodda et al, 1988;Abbas et al, 1989;Care et al, 1990). A midmolecule fragment of PTHrP was suggested to be responsible for placental transport of calcium in sheep (Care et al, 1990), a region which appeared to be present in Sparus saccus through interaction with antibody specific to the midmolecule 50-69 residues.…”

Parathyroid Hormone‐related Protein in Hypercalcaemia of Malignancy

“…This is suggested by the finding of PTHrP in lactating rat breast, its disappearance with cessation of suckling, and reappearance with its return . Biological assay of extracts of foetal and maternal ovine tissues provided evidence for the existence of PTHrP in both foetal lamb parathyroid and placenta Abbas et al, 1989;Loveridge et al, 1988;Rodda et al, 1988). Placental content of PTHrP was higher in early rather than in late pregnancy .…”

“…It is likely to consist of at least a large part of the mature 141-amino acid protein, and therefore has the potential to produce effects which can be quite distinct from those of the PTH-related part of the molecule. We have drawn attention to one such effect, on calcium transport across the placenta Rodda et al, 1988), and will summarize that evidence below. Recombinant PTHrP has recently been prepared, using a stable expression system in Escherichiu coli (Hammonds et al, 1988).…”

Parathyroid Hormone Related Protein: A Marker of Breast Tumor Progression and Outcome

“…This led to the idea that the protein may be the longpostulated signal that adapts maternal calcium metabolism to the stress of lactation. While an infusion of PTHrP can increase mammary blood flow in goats (Posser et al 1994) and sheep (Rodda et al 1988), this does not appear to alter milk production or enhance the calcium content of the milk. Moreover, there is no evidence that the plasma concentration of PTHrP induced by lactation can mobilize calcium from bone or enhance its renal reabsorption.…”