Pamidronate corrects the down-regulation of the renal parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor mRNA in rats bearing Walker tumors

Human hypercalcemia of malignancy (HHM) is generally due to the release into the circulation of parathyroid hormone-related peptide (PTHrP). PTHrP stimulates osteoclastic bone resorption and renal calcium reabsorption through the activation of a receptor similar to that of PTH (PTH-R). However, there is scarce information about the PTH-R regulation in the setting of the hypercalcemia. In the present study, we assessed the molecular basis of renal PTH-R regulation in Walker tumor-bearing rats either treated or not by a bisphosphonate, pamidronate. Twenty-seven 6-week-old rats were randomly divided into three experimental groups: WC(-)APD(-) (9 control rats), WC(+)APD(-) (9 Walker tumor-bearing rats), and WC(+)APD(+) (9 Walker tumor-bearing rats receiving 15 mg/kg/day of sodium pamidronate every day for seven days). Pamidronate induced a significant decrease in the mean tumor weight (9.3 +/- 0.8 vs 6.3 +/- 0.6 g). Seven days after the subcutaneous implantation of the Walker cells, plasma total calcium was 10.8 +/- 0.4, 16.8 +/- 0.6, and 12.9 +/- 0.6 mg/dl in WC(-)APD(-), WC(+)APD(-), and WC(+)APD(+), respectively. Plasma PTHrP concentration was undetectable, 15.9 +/- 2.6, and 7.2 +/- 1.4 pmol/l, respectively. Bone histomorphometric results showed high resorption in WC(+)APD(-), which returned below the basal level of the WC-APD-with pamidronate treatment. Densitometric analysis of Northern blots revealed that the renal PTH-R mRNA expression in WC+WPD- rats was a quarter of the levels in the WC-APD-and WC(+)APD(+) groups. WC(+)APD(-) also had a decreased PTH-stimulated cAMP production in renal membranes. The PTH-R was expressed in the Walker tumor and it was not modified by pamidronate treatment. In conclusion, the expression of PTH-R receptor mRNA is significantly reduced in the kidney of rats bearing Walker carcinoma tumor. Its regulation is tissue-specific: pamidronate, which partially corrected the hypercalcemia and elevated circulating PTHrP, normalized the PTH-R mRNA expression in the kidney but not in the tumor.