The role of the vitamin D receptor in regulating vitamin D metabolism: A study of vitamin D-dependent rickets, type II

In vitro studies and animal experiments suggest that the production of 1,25 -dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally cont rolled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a p eriod of high dose calcium therapy, 7 of the patients had normal serum calc ium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urin ary calcium/ creatinine, and renal phosphate threshold concentration were c ompared with unaffected family members that comprised the control group. Vi tamin D metabolites were measured before and after an oral load of 50,000 U /m(2) cholecalciferol. Compared with the control group, 1,25(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH- N group and even more so in the PTH-H group. 1 alpha -Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lowe r than in controls. In the PTH-H group, 1-OHase activity was even higher, p robably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an ad ditive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciproca l control of enzyme activity in man, suppressing 1-OHase and stimulating 24 -OHase activity.