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The Role of the Vitamin D Receptor in Regulating Vitamin D Metabolism: A Study of Vitamin D-Dependent Rickets, Type II

Department of Pediatrics, Rambam Medical Center, Haifa 31096, Israel; and Bone Disease Unit, Tel-Aviv Medical Center (Y.W.), Tel-Aviv 64230, Israel

Address all correspondence and requests for reprints to: Dr. Dov Tiosano, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E-mail: d_tiosano{at}rambam.health.gov.il

In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)₂D] and 24,25-(OH)₂D is reciprocally controlled by 1,25-(OH)₂D. 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 period of high dose calcium therapy, 7 of the patients had normal serum calcium, 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, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m² cholecalciferol. Compared with the control group, 1,25-(OH)₂D levels were significantly higher and 24,25-(OH)₂D levels were lower in the PTH-N group and even more so in the PTH-H group. 1-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 lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)₂D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)₂D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.

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