Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl-Terminal Ligands

Abstract

PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH1Rs. New in vitro and in vivo evidence, together with older observations extending over the past 20 yr, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion, and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH1R.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease

“…9 We disclose the limit of not having measured PTHrP but the low PTH levels observed in our hypercalcemic patients are consistent with PTHrP elevation since the IRMA assay we used for PTH evaluation does not cross-react with PTHrP. 9,17,18 Out of 151, two patients (1.3%), however, had elevated levels of both serum calcium and PTH suggesting primary hyperparathyroidism. Hyperparathyroidism is frequent in the aged population, 20 thus the association Disordered calcium metabolism and prognosis M Tucci et al with prostate cancer is not expected to be rare even if precise estimates are not presently available.…”

“…NTX was measured using a commercial kit (Osteomark, OrthoClinical Diagnostics, Rochester, NY, USA), plasma CgA was measured using an enzyme-linked immunosorbent assay kit (Dako, Glostrup, Denmark) serum PTH (intact molecule) was measured by an immunoradiometric assay (Nichols, San Juan Capistrano, CA, USA) that does not cross-react with PTHrP. 17,18 Measuring ranges, minimum detectable concentrations, intra-and interassay coefficients of variation were as follows: NTX 30-3000 nM, 20 nM, 4.4 and 6.9%; CgA 5-650 U l À1 , 2 U l À1 , 4.7 and 5.6%; PTH 2.5-2000 pg ml À1 , 2.1 pg ml À1 , 4.1 and 4.9%.…”

hPTH‐fragments (53–84) and (28–48) antagonize the stimulation of calcium release and repression of alkaline phosphatase activity by hPTH‐(1–34) in vitro

“…Since the hPTH-fragments (53-84) and (28-48) including hPTH-(7-84) do not have an effect per se on cAMP synthesis, the suppressive effect may be the result of an indirect regulation of the type I PTH/PTHRP receptor by the action of C-PTH-fragments on the C-PTH receptor. Binding experiments have shown that Cterminal PTH peptides can bind specifically and is equally displaced by PTH-(7-84) and by PTH-(1-84), but only partially displayed by PTH-(1-34) [19][20][21]. Binding data specific for PTH-(53-84) have been demonstrated [22].…”

Parathyroid Hormone Related Protein: A Marker of Breast Tumor Progression and Outcome

“…Parathyroid hormone-related protein (PTHrP) is a PTH-like calcitropic hormone, a growth factor and regulator of development (Murray et al, 2005). Tumor-derived PTHrP appears to be a crucial component of a chain of signalling events among cells of the bone microenvironment that facilitates both the destruction of bone and the growth of tumor cells (Guise et al, 1996;Thomas et al, 1999, Kozlow& Guise 2005.…”