pTH (7-84) (human)

Background: The intact parathyroid hormone (PTH) assay evaluates levels of serum 1-84 PTH and other N-terminally truncated PTH fragments, mainly PTH "7-84." This PTH molecule has been found experimentally to interfere with biological activity of PTH 1-84, perhaps through its binding to the PTH receptor complex. Therefore, assuming that high levels of PTH 7-84 are a cause of bone resistance to PTH, it has been hypothesized that a decreased 1-84 to 7-84 PTH ratio caused by a relative increase in PTH 7-84 level might help in the noninvasive diagnosis of low-turnover osteodystrophy (LTO). Methods: This study was performed in 35 patients with chronic renal failure on hemodialysis therapy who underwent bone biopsy for a histological, histomorphometric, and histodynamic study. In addition, blood samples were obtained for intact PTH, 1-84 PTH, and total PTH assays. PTH 7-84 level was obtained from the difference between total and 1-84 PTH assay results. Results: Nine patients had LTO (8 patients, adynamic bone disease; 1 patient, osteomalacia), 12 patients had hyperparathyroidism (HP), and 14 patients had mixed osteodystrophy (MO). On average, 1-84 PTH levels were approximately 60% of mean values for intact PTH. The two assays were strictly correlated. Average 1-84 to 7-84 PTH ratios were 1.57 +/- 0.85, 1.73 +/- 1.31, and 1.95 +/- 2.1 in the three histological groups (LTO, HP, and MO, respectively), with no significant difference. Conclusion: Contrary to previous expectations, results do not favor the hypothesis of a role of 7-84 PTH in bone resistance in renal osteodystrophy. The 1-84 to 7-84 PTH ratio is not a marker of LTO and is of no use in noninvasive histological diagnosis.

This review considers many new basic and clinical aspects of parathyroid hormone (PTH). We focus especially on the identification of PTH fragments and how they may relate to renal failure, diagnosis, and treatment of secondary hyperparathyroidism and renal osteodystrophy. The biosynthesis and metabolism of PTH, measurement of circulating forms of PTH, the effects of PTH on receptor activation and turnover, the relationship between PTH levels and bone turnover in renal failure in humans, and the involvement of PTH in experimental models of renal failure are discussed. Despite these developments in understanding the etiology of renal failure and the availability of new assays for bioactive PTH, no adequate surrogate for bone biopsy and quantitative bone histomorphometry has been developed.

The linear sequence of intact mammalian PTH consists of 84 amino acids, of which only the most amino(N)-terminal portion, i.e. PTH-(1-34), is required for the classical actions of the hormone on mineral ion homeostasis mediated by the type 1 PTH/PTHrP receptor (PTH1R). Like the N-terminus, the carboxyl (C)-terminal sequence of PTH is highly conserved among species, and various circulating PTH C-fragments are generated by peripheral metabolism of intact PTH or are directly secreted, in a calcium-dependent manner, by the parathyroid glands. Certain synthetic PTH C-fragments exert actions on bone and cartilage cells that are not shared by PTH-(1-34), and specific binding of PTH C-peptides has been demonstrated in bone cells in which PTH1R expression was eliminated by gene targeting. The peptide human (h) PTH-(7-84) recently was shown to inhibit the calcemic actions of hPTH-(1-34) or hPTH-(1-84) in parathyroidectomized animals. To determine whether this anticalcemic effect of hPTH-(7-84) in vivo might result from direct actions on bone, we studied its effects on both resorption of intact bone in vitro and formation of osteoclasts in primary cultures of murine bone marrow. Human (h) PTH-(7-84) (300 nM) reduced basal 72-h release of preincorporated (45)Ca from neonatal mouse calvariae by 50% (9.6 +/- 1.9% vs. 17.8 +/- 5.7%; P < 0.001) and similarly inhibited resorption induced by hPTH-(1-84), hPTH-(1-34), 1,25-dihydroxyvitamin D(3) (VitD), PGE(2), or IL-11. In 12-d murine marrow cultures, both hPTH-(7-84) (300 nM) and hPTH-(39-84) (3000 nM) lowered VitD-dependent formation of osteoclast-like cells by 70%. On the contrary, these actions of hPTH-(7-84) were not observed with the PTH1R antagonists hPTH-(3-34)NH(2) and [L(11),D-W(12),W(23),Y(36)]hPTHrP-(7-36)NH(2), which, unlike hPTH-(7-84), did inhibit PTH1R-dependent cAMP accumulation in ROS 17/2.8 cells. We conclude that hPTH-(7-84), acting via receptors distinct from the PTH1R and presumably specific for PTH C-fragments, exerts a direct antiresorptive effect on bone that may be partly due to impaired osteoclast differentiation.