Parathyroid hormone-related protein: from hypercalcemia of malignancy to developmental regulatory molecule

Parathyroid hormone-related protein (PTHrP) was originally discovered because of its role in humoral hypercalcemia of malignancy (HHM), a common metabolic complication of many types of cancer. In HHM, PTHrP is released into the circulation by malignant cells and cross reacts with parathyroid hormone (PTH) receptors in bone and kidney, which results in hypercalcemia. In recent years, it has become clear that PTHrP is a normal product of many adult and fetal tissues where it appears to act in an autocrine and/or paracrine fashion to regulate organogenesis. This article explores the molecular evolution of PTHrP and how this understanding has begun to shed some light on the molecular mechanisms responsible for the biochemical manifestations of HHM. In addition, the normal biological function of PTHrP is discussed, with an emphasis on its role as a developmental regulatory molecule.