Increased sensitivity to 1,25(OH)2D3 in bone from genetic hypercalciuric rats.
As a model of human hypercalciuria, we have selectively inbred genetic hypercalciuric stone-forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is eight to nine times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption, which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors (VDR). When GHS rats are fed a low-calcium diet, the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3, we cultured calvariae from neonatal (2- to 3-day-old) GHS and control rats with or without 1,25(OH)2D3 or parathyroid hormone (PTH) for 48 h at 37 degrees C. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, whereas control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a fourfold increase in the level of VDR in GHS calvariae compared with control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of VDR suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat.
Krieger
N S
NS
Department of Medicine, University of Rochester School of Medicine, New York 14642, USA.
Stathopoulos
V M
VM
Bushinsky
D A
DA
D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000652:urine*; D046508:Culture Techniques; D004351:Drug Resistance; D005260:Female; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D012886:Skull / Q000187:drug effects / Q000378:metabolism
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium