Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D3-1α-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy

Abstract

In patients with humoral hypercalcemia of malignancy (HHM), serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) are generally low, although the pathophysiology of the impaired vitamin D metabolism is not fully understood. In the present study, we have investigated vitamin D metabolism in our newly developed rat model of HHM in which a human infantile fibrosarcoma producing parathyroid hormone-related protein (PTHrP), named OMC-1, was inoculated s.c. into athymic nude rats. In OMC-1-bearing rats, the serum concentration of 1,25(OH)2D was markedly reduced when the animals exhibited severe hypercalcemia (Ca ≥ 15 mg/dl), while it was rather elevated in those with mild hypercalcemia. To further examine whether serum Ca levels affect 1,25(OH)2D concentration, we administered bisphosphonate YM529 to OMC-1-bearing rats when they exhibited severe hypercalcemia. The restoration of the serum Ca level by administration of YM529 was accompanied by a marked increase in the 1,25(OH)2D level, suggesting that the serum Ca level itself plays an important role in the regulation of the 1,25(OH)2D level in these rats. On the other hand, when the OMC-1-bearing rats were treated with a neutralizing antibody against PTHrP, serum 1,25(OH)2D levels remained low despite the reduction in serum Ca levels. Expression of 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) in kidney was decreased in OMC-1-bearing rats with severe hypercalcemia, and markedly enhanced after treatment with bisphosphonate. This enhancement in 1α-hydroxylase expression was not observed after treatment with the antibody against PTHrP. These results suggest that PTHrP was responsible for the enhanced expression of 1α-hydroxylase in YM529-treated rats, and that hypercalcemia played a role in reducing the serum 1,25(OH)2D level in OMC-1-bearing rats by suppressing the PTHrP-induced expression of the 1α-hydroxylase gene.