Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

Abstract

A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

Parathyroid Hormone‐related Protein in Hypercalcaemia of Malignancy

“…The consistently lesser potency of PTHrP(1-34) which we have observed in this system has also been noted in studies of stimulation of resorption in new born mouse calvaria (Lorenzo et al, 1988). Although there is some disagreement about the relative potencies of PTHrP(1-34) and PTH(1-34) in stimulating bone resorption (Yates et al, 1988), there can be little doubt that PTHrP( 1-34) is capable of resorbing bone. This has been confirmed in vivo also by the demonstration that injection of PTHrP( 1-34) results in hypercalcaemia in rats and mice (Horiuchi er al., 1987;Yates et al, 1988).…”

“…Although there is some disagreement about the relative potencies of PTHrP(1-34) and PTH(1-34) in stimulating bone resorption (Yates et al, 1988), there can be little doubt that PTHrP( 1-34) is capable of resorbing bone. This has been confirmed in vivo also by the demonstration that injection of PTHrP( 1-34) results in hypercalcaemia in rats and mice (Horiuchi er al., 1987;Yates et al, 1988). Experiments were also carried out in the isolated perfused rat kidney to determine responses to PTHrP( 1-34).…”

Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia

“…The pathophysiology of hypercalcaemia differs depending on the tumour type, but two broad categories are recognized (Mundy and Martin, 1982). In humorally mediated hypercalcaemia, the elevation in blood calcium is most often caused by release of parathyroid hormone-related protein (PTHrP), which causes a generalized increase in osteoclastic bone resorption and increased reabsorption of calcium by the renal tubule (Yates et al, 1988;Ralston, 1987;Martin and Suva, 1989). Alternatively, hypercalcaemia may arise as the result of tumour metastases in bone, which stimulate osteoclastic bone resorption on a multifocal basis, with release of calcium at a rate in excess of that which can be excreted by the kidney.…”

The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling

“…To measure responses of murine calvarial bone to PTH, we followed the procedures developed by Boyce and coworkers (13,14,36). Synthetic human PTH(1-34) was obtained from Bachem California Inc. (Torrance, California, USA) and dissolved in vehicle (1 mM HCl, 0.1% BSA).…”