Structure-Function Relationships in the Vitamin D Endocrine System*

Bouillon, Roger; Okamura, William H.; Norman, Anthony W.

doi:10.1210/edrv-16-2-200

Cited by 497 publications

(478 citation statements)

References 122 publications

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“…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)(2)(3). Vitamin D is absorbed from the diet and generated in skin by exposure to ultraviolet light.…”

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confidence: 99%

“…The secosteroid is transported in blood bound to vitamin D-binding protein (4) and hydroxylated in the liver at the 25-position by a vitamin D 25-hydroxylase (CYP27) (5). The metabolite 25-hydroxyvitamin D is further hydroxylated at the 1␣-position to produce the active moiety, 1,25-dihydroxyvitamin D (1,25(OH) 2 D) 1 (1)(2)(3). The enzyme catalyzing the production of 1,25(OH) 2 D is 25-hydroxyvitamin D 1␣-hydroxylase (1␣(OH)ase or CYP27B1).…”

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confidence: 99%

“…A number of tissues can synthesize 1,25(OH) 2 D, but the kidney is the principal site generating the circulating hormone. The renal 1␣(OH)ase is known to be tightly regulated by several factors including parathyroid hormone (PTH), calcium, phosphorus, and 1,25(OH) 2 D per se (1)(2)(3). An alternate site of hydroxylation of 25-hydroxyvitamin D can be catalyzed by the enzyme 25-hydroxyvitamin D 24-hydroxylase (24(OH)ase or CYP24), yielding the metabolite 24,25-dihydroxyvitamin D (13).…”

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confidence: 99%

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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

357

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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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

357

328

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“…13). Generally, these analogues have been screened in terms of the affinity for the VDR and vitamin D-binding protein.…”

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confidence: 99%

“…Certain synthetic analogues like 22-oxa-1␣,25(OH) 2 D 3 appear to succeed in the dissection of various effects of 1␣,25(OH) 2 D 3 by taking advantage of the difference in binding to the VDR and vitamin D-binding protein and metabolic pathway (14). To date, however, no anti-vitamin D compounds that oppose the genomic actions of the natural ligand 1␣,25(OH) 2 D 3 , have been reported (13). We have recently synthesized a novel analogue 23(S)-25-dehydro-1␣-hydroxyvitamin D 3 -26,23-lactone (TEI-9647) and found that it efficiently blocks the differentiation of HL-60 cells induced by 1␣,25(OH) 2 D 3 (15).…”

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confidence: 99%

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Ozono

Saito

Miura

et al. 1999

Journal of Biological Chemistry

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5). The effects exerted via the VDR are called genomic effects, in contrast to non-genomic effects, which means that 1␣,25(OH) 2 D 3 acts within a short period without transcription of target genes (6). The VDR-mediated effects of 1␣,25(OH) 2 D 3 in vivo are well known, since there is a human disease associated with the abnormality of the VDR gene, which is called vitamin D dependence type II (7). In addition, a mouse model of the disease was generated by targeting the VDR gene and has been used the analysis of the VDR function in vivo (8, 9).The VDR consists of several functional domains such as DNA-binding and ligand-binding domains (1, 2). Heterodimerization of the VDR with retinoid X receptor (RXR) is also important for the binding to a vitamin D-responsive element (VDRE) with high affinity (1, 2, 5, 10). Ligand-dependent activation of transcription requires the extreme C-terminal portion of the VDR, which is designated as the AF-2 core domain (1,11,12). The interaction of these domains is required for the VDR to regulate the transcription of target genes.A large number of 1␣,25(OH) 2 D 3 analogues have been synthesized in an attempt to dissociate various biological activities including hypercalcemic effects, bone-forming effects, and promotion of cell differentiation (for review, see Ref. . Although this differentiation is believed to be mediated by VDR, more direct evidence is needed to establish whether TEI-9647 is an antagonist of the genomic action of vitamin D. Antagonists, if obtained, would be useful for determining whether each of the effects of 1␣,25(OH) 2 D 3 is mediated by the VDR. In addition, a potentially promising way to achieve the differential effect of vitamin D is to use analogues that antagonize particular effects elicited by vitamin D.In contrast to the case of VDR, several antagonists have been reported for other members of the nuclear hormone receptor superfamily, and have contributed to the understanding of the

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Vitamin D and Retinopathy in Adults With Diabetes Mellitus

Patrick¹,

Visintainer²,

Shi³

et al. 2012

Arch Ophthalmol

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To explore a hypothesized association between vitamin D inadequacy and diabetic retinopathy.Methods: This cross-sectional study analyzed data from individuals aged 40 years and older with diabetes mellitus who participated in the interview and medical examination components of the Third National Health and Nutrition Examination Survey conducted from October 1, 1988, through September 30, 1994 The relationship between diabetic retinopathy and serum 25hydroxyvitamin D concentration was evaluated using regression analysis in the presence of demographic and clinical covariates, such as age, race, obesity, and persistent hyperglycemia.Results: On the basis of the 1790 adults with diabetes who met the study's inclusion criteria, the percentage of individuals with vitamin D deficiency increased with se-verity of retinopathy: no retinopathy, 27.9%; mild, 28.2%; moderate to severe, 43.2%; and proliferative, 64.6% (P=.01). Regression analysis of retinopathy severity vs serum 25-hydroxyvitamin D concentration did not demonstrate a statistically significant relationship between the two variables (P =.07).Conclusions: This study found an association between severity of diabetic retinopathy and prevalence of vitamin D deficiency, but the findings were inconclusive about the existence of a relationship between retinopathy severity and serum 25-hydroxyvitamin D concentration. Given previous research indicating possible antiinflammatory and antiangiogenic properties of vitamin D, the connection between vitamin D and diabetic retinopathy warrants further study.

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Structure-Function Relationships in the Vitamin D Endocrine System*

Cited by 497 publications

References 122 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

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Vitamin D and Retinopathy in Adults With Diabetes Mellitus

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