PARATHYROID HORMONE-RELATED PROTEIN AND CALCIUM-PHOSPHATE METABOLISM

There is marked homology between the parathyroid hormone (PTH) and PTH -related protein (PTHrP) molecules at the amino terminal but the rest of the molecules are quite different, providing immunologically distin ct peptides. However, they interact with the same receptor. Thus, PTHr P mediates biological actions reminiscent of PTH. PTHrP gene is a sing le copy gene, producing one to three mRNA transcripts through alternat ive splicing of the carboxy terminal, encoding peptides of 139, 141 or 173 amino acids. Having been recently isolated from malignant tumours , PTHrP is now considered to be the major mediator of humoral hypercal caemia of malignancy (HHM). The PTH-like effects of PTHrP on the kidne y and bone have been well characterized. The increase in renal tubular calcium reabsorption and the reduction in tubular phosphate reabsorpt ion with a concomitant rise in nephrogenous cyclic AMP constitute the pathophysiological changes in the renal handling of calcium and phosph ate in HHM. The osteotropic contribution to the malignant hypercalcaem ia has been validated by enhanced osteoclastic bone resorption - an in direct effect of the amino terminal portion of the PTHrP molecule on o steoblasts. However, PTHrP has also been detected in a large number of normal adult tissues/organs as well as in human and animal fetuses. F etal plasma calcium is higher than maternal and this is achieved by ac tive transport of calcium across the placenta. Using ovine placental p erfusion models, PTHrP, which is believed to originate from fetal para thyroid glands and the placenta itself, has been demonstrated to susta in this calcium gradient. Active placental transport of magnesium, but not phosphate, was also shown to be enhanced by PTHrP. In lactating r at mammary gland, PTHrP mRNA is expressed in response to the sucking s timulus, an effect probably mediated by a rise in the plasma level of prolactin. PTHrP, in various molecular sizes, is present in high conce ntrations in milk. Potential roles of mammary-derived PTHrP include ac tive calcium translocation from blood to milk and/or the facilitation of intestinal calcium absorption in the newborn animal. There is recen t evidence for an opposing osteotropic action mediated by the carboxy terminal of PTHrP which directly inhibits osteoclastic function. This would act synergistically with the relative fetal hypercalcaemia to en sure adequate bone mineralization in the developing fetus. This postul ate, as with the other potential physiological role(s) of PTHrP in fet al and neonatal calcium and phosphate metabolism, now awaits further r esearch.