Expression of the vitamin D receptor in the intestine and kidney of osteopetrotic rats.

Osteopetrosis describes a heterogeneous group of metabolic bone disorders characterized by a generalized skeletal sclerosis. Because reduced bone resorption coexists with elevated plasma levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D] in several osteopetrotic animals and children, skeletal resistance to this hormone has been proposed. In some mutations, such as the osteopetrotic (op) rat, the inability of 1,25-(OH)2D to elicit a skeletal response has been demonstrated. It is not known whether this resistance is localized to the skeleton or involves all 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 Scatchard analysis demonstrated a delayed pattern of VDR expression in the intestine of op rats compared with their normal littermates; unoccupied VDR levels were up-regulated in op mutants from 5-8 weeks. Western analysis of 6-week-old mutant and normal intestinal, chromatin-associated protein revealed that total VDR levels were consistently and significantly elevated in all of the mutants examined. In op kidney, VDR numbers did not change as a function of age and were significantly down-regulated from 2-6 weeks of age compared with age-matched normal littermates. 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)2D in op mutants is not the result of a generalized receptor defect resulting in reduced numbers or affinity. Furthermore, the up-regulation of intestinal VDR observed in older (5- to 8-week-old) mutants may reflect a compensatory mechanism to help establish and maintain normal serum calcium and phosphorus levels.