EXPRESSION OF THE VITAMIN-D RECEPTOR IN THE INTESTINE AND KIDNEY OF OSTEOPETROTIC RATS

Osteopetrosis describes a heterogeneous group of metabolic bone disord ers characterized by a generalized skeletal sclerosis. Because reduced bone resorption coexists with elevated plasma levels of 1,25-dihydrox yvitamin D [1,25-(OH)(2)D] in several osteopetrotic animals and childr en, skeletal resistance to this hormone has been proposed. In some mut ations, such as the osteopetrotic (op) rat, the inability of 1,25-(OH) (2)D to elicit a skeletal response has been demonstrated. It is not kn own whether this resistance is localized to the skeleton or involves a ll target tissues. This study examined vitamin D receptor (VDR) status in the intestine and kidney from op rats and their normal littermates from 2-8 weeks of age. Quantitation of unoccupied VDR levels by Scatc hard analysis demonstrated a delayed pattern of VDR expression in the intestine of op rats compared with their normal littermates; unoccupie d VDR levels were up-regulated in op mutants from 5-8 weeks. Western a nalysis of 6-week-old mutant and normal intestinal, chromatin-associat ed protein revealed that total VDR levels were consistently and signif icantly elevated in all of the mutants examined. In op kidney, VDR num bers did not change as a function of age and were significantly down-r egulated from 2-6 weeks of age compared with age-matched normal litter mates. VDR affinity was similar in age-matched mutant and normal rats in both the intestine and kidney. In summary, these data suggest that skeletal resistance to 1,25-(OH)(2)D in op mutants is not the result o f a generalized receptor defect resulting in reduced numbers or affini ty. Furthermore, the up-regulation of intestinal VDR observed in older (5- to 8-week-old) mutants may reflect a compensatory mechanism to he lp establish and maintain normal serum calcium and phosphorus levels.