Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in. 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate ge ne. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arisin g from post-translation al endoproteolytic cleavage of the initial PTHrP tr anslation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologi c functions and probably their own receptors. The type I PTHrP receptor, bi nding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. P THrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent asp ects of PTHrP pharmacology and physiology, including: (a) the identificatio n of new peptides and receptors of the PTH/PTHrP system; (b) the recently d iscovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and develop mental actions of PTHrP in the cardiovascular and the renal glomerulovascul ar systems; (d) the role of PTHrP as a regulator of pancreatic beta cell gr owth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These ne w advances have contributed to a better understanding of the pathophysiolog ical role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.