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 tumorbearing 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.

Key words

Walker Carcinoma - Hypercalcemia - Cyclic AMP - Bone Resorption - Sodium Pamidronate