Pamidronate corrects the down-regulation of the renal parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor mRNA in rats bearing Walker tumors.
Hormone and Metabolic Research(1998)
摘要
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.
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关键词
Walker carcinoma,hypercalcemia,cyclic AMP,bone resorption,sodium pamidronate
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