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

Abstract

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 gene. 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 arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identi®cation of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH

“…This enhancement in the PTH-induced hypotensive response presumably reflects a defect in the capacity of the PD-PTHR1 to desensitize and/or downregulate in vasculature cells following PTH activation. The PTHR1 is known to be expressed in vascular smooth muscle and endothelial cells and to mediate reductions in vascular tone (18). A defect in desensitization is also likely reflected by the higher basal and PTH-induced cAMP signaling responses observed for the PD-PTHR1 in our in vitro assays, and likely contributes to the normalization of the blood Ca 2+ and Pi levels observed in the PD mice in the context of their lower endogenous levels of PTH (1-84), as found previously (21).…”

“…7B). As PTH is known to have hypotensive effects on the vasculature (18), and previous studies in rats show that PTH-induced reductions in systemic blood pressure can result in reduced glomerular blood flow (19), we assessed the effects of PTH administration on systemic blood pressure in WT and PD mice (20). Following a brief i.v.…”

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

“…sc-9680) recognizes full-length and NH 2 -terminal PTHrP (aa 1-34), whereas the rabbit anti-PTHrP (Calbiochem, Merck Chemicals Limited; cod. PC09) is specific for mid-region PTHrP (aa [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. Briefly, blotted polyvinyl difluoride (PVDF) membranes (Bio-Rad, Milan, Italy) were incubated with goat or rabbit anti-PTHrP and mouse anti-PTH-R1 mAbs (Santa Cruz Biotechnology), then with secondary antibodies and finally revealed by enhanced chemiluminescence (ECL Plus; GE Healthcare, Milan, Italy).…”

Dysplasies osseuses héréditaires et voies de signalisation associées aux récepteurs FGFR3 et PTHR1

“…Le PTHrP, décrit initialement dans des hypercalcémies humorales malignes, n'est pas détectable physiologiquement dans la circulation systémique. Comme le PTHR1, il est exprimé dans de nombreux tissus et exerce de multiples actions physiologiques qu'il n'est pas possible de résumer dans cette revue (voir [28] et revue de J.J. Helwig à paraître dans médecine/sciences). En particulier, c'est un régulateur de la prolifération et de la différencia-tion cellulaire, notamment lors du développement osseux enchondral.…”