DEFINING THE ROLES OF PARATHYROID HORMONE-RELATED PROTEIN IN NORMAL PHYSIOLOGY

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which caus es the common paraneoplastic syndrome humoral hypercalcemia of maligna ncy. Since the identification of the peptide in 1982 and the cloning o f the cDNA in 1987, it has become clear that PTHrP is a prohormone tha t is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only i n cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalce mia of malignancy in which PTHrP plays the role of a classical ''endoc rine'' hormone, under normal circumstances PTHrP plays predominantly p aracrine and/or autocrine roles. These apparent physiological function s are also complex and appear to include 1) regulation of smooth muscl e (vascular, intestinal, uterine, bladder) tone, 2) regulation of tran sepithelial (renal, placental, oviduct, mammary gland) calcium transpo rt, and 3) regulation of tissue and organ development, differentiation , and proliferation. In this review, the dis covery of PTHrP, the stru cture of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.