Eberhard Blind

Circulating levels of midregional parathyroid hormone‐related protein in hypercalcaemia of malignancy

OBJECTIVE We have developed and evaluated a sensitive radioimmunoassay directed against the midregional part of parathyroid hormone‐related protein (PTHrP), which is involved in the syndrome of humoral hypercalcaemia of malignancy.

Tumor necrosis factor α inhibits the stimulatory effect of the parathyroid hormone-related protein on cyclic AMP formation in osteoblast-like cells via protein kinase C+

Tumor necrosis factor α (TNF α) and parathyroid hormone-related protein (PTHrP) are both factors that have been implicated in the mechanism of hypercalcemia of malignancy. In this study we investigated the effect of TNF α on the PTHrP-stimulated accumulation of intracellular cyclic AMP in osteoblast-like cells. In the clonal cell line Saos-2 and in primary cell cultures from fetal rat calvaria, PTHrP-stimulated accumulation of cAMP was time- and dose-dependently inhibited by exposure to TNF α. Significant inhibition occurred at concentrations as low as 2 × 10−12 M and was maximal at 1 × 10−9 M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF α was probably mediated by protein kinase C , since the phorbol ester PMA mimicked the effect of TNF α, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF α. In conclusion, these observations suggest a possible mechanism by which TNF α may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy.

Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the walker carcinosarcoma 256 rat model

In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect.