Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

Fraser, Donald R.; Kooh, Sang Whay; Kind, H P; Holick, Michael F.; Tanaka, Yoko; DeLuca, Hector F.

doi:10.1056/nejm197310182891601

Cited by 392 publications

(61 citation statements)

References 36 publications

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“…After weaning, mice, fed a diet of regular mouse chow, developed hyperparathyroidism, retarded growth, and the skeletal abnormalities characteristic of rickets. These abnormalities mimic those described in the human genetic disorder vitamin D-dependent rickets type I (also called pseudovitamin D deficiency rickets) (18,19). Several laboratories have also reported mouse models with targeted ablation of the VDR gene (VDR Ϫ/Ϫ ) (20 -22).…”

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confidence: 55%

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

Panda¹,

Miao²,

Bolivar

et al. 2004

Journal of Biological Chemistry

356

328

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We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH) 2 D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1␣-hydroxylase (1␣(OH)ase ؊/؊ ) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH) 2 D 3 , which normalized calcium in the 1␣(OH)ase ؊/؊ mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH) 2 D 3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH) 2 D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH) 2 D/VDR system. These studies indicate that the calcium ion and the 1,25(OH) 2 D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.Vitamin D plays a major role in modulating calcium and skeletal homeostasis and exerts a significant influence on the growth and differentiation of a variety of tissues (1-3). Vitamin D is absorbed from the diet and generated in skin by exposure to ultraviolet light. The secosteroid is transported in blood bound to vitamin D-binding protein (4)

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confidence: 55%

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

Panda¹,

Miao²,

Bolivar

et al. 2004

Journal of Biological Chemistry

356

328

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“…Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10). VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.…”

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confidence: 99%

“…VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.…”

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confidence: 99%

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vanhooke

Prahl

Kimmel-Jehan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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. The second hydroxylation is catalyzed by the 25-hydroxyvitamin D 3 -1␣-hydroxylase (1␣-hydroxylase), a mitochondrial cytochrome P450 enzyme that is the product of the CYP27B1 gene (2-6). Activity of 1␣-hydroxylase is tightly regulated through complex mechanisms that depend on the circulating levels of calcium, phosphorus, parathyroid hormone, and 1,25(OH) 2 D 3 .Mutations in the 1␣-hydroxylase gene are known to cause vitamin D-dependency rickets type I (VDDR-I) (2, 7-9). Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10). VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.The experiments reported by Fraser and Kodicek in 1970 (12) were the first to demonstrate the kidney as the major, if not the only, tissue in which 1,25(OH) 2 D 3 is produced under normal physiological conditions. Over the next several years, extrarenal production of 1,25(OH) 2 D 3 was convincingly demonstrated in pregnant nephrectomized rats and in an anephric patient suffering from sarcoidosis (13-15). In these cases, synthesis was localized to the placenta and the sarcoid macrophages (14,16,17). Production of 1,25(OH) 2 D 3 at other sites has remained a subject of much investigation. A number of research groups have reported 1␣-hydroxylase activity in cultured cells, including those of the skin, bone, cartilage, intestine, prostate, and vascular epithelium (18 -25). Bikle et al. (26) have also reported 1,25(OH) 2 D 3 production in perfused flaps of porcine skin. Local production of 1,25(OH) 2 D 3 has been proposed to regulate cellular function and͞or differentiation in an autocrine or paracrine fashion (18,19,24,27,28), and it has been suggested that keratinocytes could supply 1,25(OH) 2 D 3 to the systemic circulation when renal production of the hormone is impaired (26,29). Production of extrarenal 1,25(OH) 2 D 3 in these experiments is not supported, however, by in vivo metabolic studies in nephrectomized nonpregnant rats. In these studies, two independent research groups were unable to detect 3 H-1,25(OH) 2 D 3 in the tissue or plasma after administering a dose of 3 H-25-OH-D 3 of high specific radioactivity (30,31). These conflicting results demonstrate a need for further investigation of the in vivo expression of the 1␣-hydroxylase. We have approached such an investigation by using gene targeting to replace the 1␣-hydroxylase coding sequence with a bacterial lacZ gene controlled by the 1␣-hydroxylase promoter. The lacZ gene codes for ␤-galactosidase, whose activity is readily detected in situ through histochemical staining with X-Gal (32). Herein we report the successful production of 1␣-hydroxylase null mice harboring the lacZ gene and present our analysis of in vivo 1␣-hydroxylase...

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“…8 Se deberia a un defecto enzimatico congenito con deficit de la 1 <* hidroxilasa renal, necesaria para la conversion del 25 hidroxicolecalciferol a 1,25 dihidroxicolecalciferol. 9 ' lt} Se caracteriza por raquitismo de comienzo precoz, con hipocalcemia dificil de corregir. Se ha cornunicado que responden bien al tratamiento ya sea con dosis farmacologicas de vitamina D2 o con dosis fisio!6gicas del metabolito 1 ^ hidroxilado, lograndose la correccion clinica, bioqui'mica y radiologica.…”

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Tratamiento con 1,25 dihidroxicolecalciferol (DHCC) en niños con diferentes formas de raquitismo resistente

Eggers

Beas²

1982

Rev. chil. pediatr.

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The response ot different torn is ot Vitamin D ressistant rickets to 1,25 Dihydroxicholecalcipherol was studied.Eight patients with isolated hypophosphernia showed good clinical response with partial radiograph ic resolution, diminution ot serum ulcaline phosphatase and persistence oihipophosphemia.In one child with chronic renal disease and hypoealcemic rickets a good clinical, radiological and biochemical response \v;is observed.

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Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

Cited by 392 publications

References 36 publications

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Tratamiento con 1,25 dihidroxicolecalciferol (DHCC) en niños con diferentes formas de raquitismo resistente

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Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

Cited by 392 publications

References 36 publications

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

Tratamiento con 1,25 dihidroxicolecalciferol (DHCC) en niños con diferentes formas de raquitismo resistente

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CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin