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 distinct peptides. However, they interact with the same receptor. Thus, PTHrP mediates biological actions reminiscent of PTH. PTHrP gene is a single copy gene, producing one to three mRNA transcripts through alternative 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 hypercalcaemia of malignancy (HHM). The PTH-like effects of PTHrP on the kidney and bone have been well characterized. The increase in renal tubular calcium reabsorption and the reduction in tubular phosphate reabsorption with a concomitant rise in nephrogenous cyclic AMP constitute the pathophysiological changes in the renal handling of calcium and phosphate in HHM. The osteotropic contribution to the malignant hypercalcaemia has been validated by enhanced osteoclastic bone resorption--an indirect effect of the amino terminal portion of the PTHrP molecule on osteoblasts. However, PTHrP has also been detected in a large number of normal adult tissues/organs as well as in human and animal fetuses. Fetal plasma calcium is higher than maternal and this is achieved by active transport of calcium across the placenta. Using ovine placental perfusion models, PTHrP, which is believed to originate from fetal parathyroid glands and the placenta itself, has been demonstrated to sustain this calcium gradient. Active placental transport of magnesium, but not phosphate, was also shown to be enhanced by PTHrP.(ABSTRACT TRUNCATED AT 250 WORDS)