24-25-dihydroxyvitamin-d-3 and Alopecia

Topics: 24,25-Dihydroxyvitamin D 3; Administration, Oral; Age Factors; Alopecia; Bone and Bones; Calcitriol; Calcium; Dihydroxycholecalciferols; Ergocalciferols; Female; Humans; Hypophosphatemia, Familial; Male; Minerals; Pedigree; Phosphorus; Tooth Abnormalities

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adolescent; Adult; Alopecia; Animals; Bone and Bones; Calcitriol; Calcium; Cell Nucleus; Cells, Cultured; Child; Child, Preschool; Cytochrome P-450 Enzyme System; Dihydroxycholecalciferols; Drug Resistance; Female; Fibroblasts; Humans; Hypocalcemia; Hypophosphatemia, Familial; Male; Pregnancy; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)(2)D(3) in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)(2)D(3).

Topics: 24,25-Dihydroxyvitamin D 3; Alopecia; Animals; beta-Galactosidase; Binding Sites; Calcitriol; Calcium; Diet; DNA; Female; Gene Expression Regulation; Growth Disorders; Homeostasis; Homozygote; Hyperparathyroidism; Kidney; Male; Mice; Mice, Mutant Strains; Receptors, Calcitriol; Rickets; Sequence Deletion; Zinc Fingers

Three patients with clinically different severities of vitamin D-dependent rickets, type II, with alopecia, which is 1,25-dihydroxyvitamin D-receptor-defect rickets and is particularly resistant to treatment with calciferol analogues, were treated with large doses of 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) and 2 g of calcium lactate. Except for the alopecia, all of the abnormalities of patients 1 and 2 were reversed by treatment with 3 micrograms/kg/d of 1 alpha-(OH)D3, and those of patient 3, who had the severest manifestations, were reversed by treatment with 6 micrograms/kg/d. The serum 24,25-dihydroxyvitamin D concentrations of the three patients were low before treatment and those of patients 1 and 2 increased during treatment. These findings suggest that in patients 1 and 2, 25-hydroxyvitamin D-24-hydroxylase was stimulated via a 1,25-dihydroxyvitamin D-receptor-mediated system by treatment with 1 alpha-(OH)D3.

Topics: 24,25-Dihydroxyvitamin D 3; Alkaline Phosphatase; Alopecia; Calcium; Child, Preschool; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Hypophosphatemia, Familial; Lactates; Lactic Acid; Male; Phosphorus; Receptors, Calcitriol; Receptors, Steroid

Two unrelated patients, aged 22 months and 31 months, with alopecia and rickets resistant to 1,25-dihydroxyvitamin D (1,25-(OH)2D] (vitamin D-dependency type II) presented with similar biochemical and radiologic features. They were treated with large doses of vitamin D3 derivatives [25-hydroxyvitamin D3 (25-(OH)D3), 1,25-(OH)2D3, and 1 alpha-hydroxyvitamin D3] for 28 months and 6 yr, respectively. In both patients, serum 1,25-(OH)2D levels remained high (approximately 10- to 100-fold normal) during the different therapeutic regimens. Circulating 1,25-(OH)2D and 24,25-dihydroxyvitamin D levels at various stages of the disease suggested in these children disturbances in the regulation of 25-hydroxyvitamin D (25(OH)D) 1 alpha- and 24-hydroxylase systems. In one child, all therapeutic trials were unsuccessful. Studies of her cultured skin fibroblasts showed low capacity (10% normal) for saturable (presumably receptor mediated) nuclear uptake of tritiated 1,25-(OH)2D3; the uptake process of nucleus associated 1,25-(OH)2D3 was normal in apparent affinity for 1,25-(OH)2D3 and in sedimentation velocity of nucleus-associated hormone. In the second child, correction of biochemical abnormalities, healing of rickets, and catch-up growth were obtained during similar therapeutic trials up to the age of 6 yr when a relapse occurred. This relapse has persisted for 2 yr in spite of similar or higher circulating concentrations of 25-(OH)D and 1,25-(OH)2D than those obtained previously when she was responsive to therapy. In her cultured skin fibroblasts, saturable high affinity nuclear uptake of 1,25(OH)2D was unmeasurable.. 1) distinct patterns of clinical response can occur in patients with the syndrome of vitamin D-dependency type II, and can be associated with differing abnormalities in interaction of 1,25-(OH)2D3 with cultured skin fibroblasts; 2) aggravation of the resistance to 1,25-(OH)2D3 may occur during long term therapy in some patients.

Topics: 24,25-Dihydroxyvitamin D 3; Alopecia; Calcitriol; Child, Preschool; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Hypophosphatemia, Familial; Infant; Receptors, Calcitriol; Receptors, Steroid