Current Understanding of the Molecular Actions of Vitamin D

1998 ◽  
Vol 78 (4) ◽  
pp. 1193-1231 ◽  
Author(s):  
GLENVILLE JONES ◽  
STEPHEN A. STRUGNELL ◽  
HECTOR F. DeLUCA
Keyword(s):  
Vitamin D ◽  
Parathyroid Gland ◽  
Active Form ◽  
Current Understanding ◽  
Target Cells ◽  
Female Reproduction ◽  
Physiological Level ◽  
Dihydroxyvitamin D ◽  
Hydroxylation Reaction

Jones, Glenville, Stephen A. Strugnell, and Hector F. DeLuca. Current Understanding of the Molecular Actions of Vitamin D. Physiol. Rev. 78: 1193–1231, 1998. — The important reactions that occur to the vitamin D molecule and the important reactions involved in the expression of the final active form of vitamin D are reviewed in a critical manner. After an overview of the metabolism of vitamin D to its active form and to its metabolic degradation products, the molecular understanding of the 1α-hydroxylation reaction and the 24-hydroxylation reaction of the vitamin D hormone is presented. Furthermore, the role of vitamin D in maintenance of serum calcium is reviewed at the physiological level and at the molecular level whenever possible. Of particular importance is the regulation of the parathyroid gland by the vitamin D hormone. A third section describes the known molecular events involved in the action of 1α,25-dihydroxyvitamin D3 on its target cells. This includes reviewing what is now known concerning the overall mechanism of transcriptional regulation by vitamin D. It describes the vitamin D receptors that have been cloned and identified and describes the coactivators and retinoid X receptors required for the function of vitamin D in its genomic actions. The presence of receptor in previously uncharted target organs of vitamin D action has led to a study of the possible function of vitamin D in these organs. A good example of a new function described for 1α,25-dihydroxyvitamin D3 is that found in the parathyroid gland. This is also true for the role of vitamin D hormone in skin, the immune system, a possible role in the pancreas, i.e., in the islet cells, and a possible role in female reproduction. This review also raises the intriguing question of whether vitamin D plays an important role in embryonic development, since vitamin D deficiency does not prohibit development, nor does vitamin D receptor knockout. The final section reviews some interesting analogs of the vitamin D hormone and their possible uses. The review ends with possible ideas with regard to future directions of vitamin D drug design.

scholarly journals Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer

2013 ◽  
Vol 20 (2) ◽  
pp. R31-R47 ◽  
Author(s):  
Carlien Leyssens ◽  
Lieve Verlinden ◽  
Annemieke Verstuyf
Keyword(s):  
Colorectal Cancer ◽  
Vitamin D ◽  
Side Effects ◽  
Active Form ◽  
Malignant Cell ◽  
Inverse Association ◽  
Dihydroxyvitamin D ◽  
Cancer Types ◽  
Epidemiological Link

The active form of vitamin D3, 1,25-dihydroxyvitamin D3(1,25(OH)2D3), is mostly known for its importance in the maintenance of calcium and phosphate homeostasis. However, next to its classical effects on bone, kidney and intestine, 1,25(OH)2D3also exerts antineoplastic effects on various types of cancer. The use of 1,25(OH)2D3itself as treatment against neoplasia is hampered by its calcemic side effects. Therefore, 1,25(OH)2D3-derived analogs were developed that are characterized by lower calcemic side effects and stronger antineoplastic effects. This review mainly focuses on the role of 1,25(OH)2D3in breast, prostate and colorectal cancer (CRC) and the underlying signaling pathways. 1,25(OH)2D3and its analogs inhibit proliferation, angiogenesis, migration/invasion and induce differentiation and apoptosis in malignant cell lines. Moreover, prostaglandin synthesis and Wnt/b-catenin signaling are also influenced by 1,25(OH)2D3and its analogs. Human studies indicate an inverse association between serum 25(OH)D3values and the incidence of certain cancer types. Given the literature, it appears that the epidemiological link between vitamin D3and cancer is the strongest for CRC, however more intervention studies and randomized placebo-controlled trials are needed to unravel the beneficial dose of 1,25(OH)2D3and its analogs to induce antineoplastic effects.

scholarly journals The Vitamin D System in Humans and Mice: Similar but Not the Same

Reports ◽  
2020 ◽  
Vol 3 (1) ◽  
pp. 1
Author(s):  
Ewa Marcinkowska
Keyword(s):  
Vitamin D ◽  
Target Gene ◽  
Active Form ◽  
Uvb Radiation ◽  
Immune Functions ◽  
Vdr Gene ◽  
Anatomy And Physiology ◽  
Dihydroxyvitamin D ◽  
Bone Maintenance

Vitamin D is synthesized in the skin from 7-dehydrocholesterol subsequently to exposure to UVB radiation or is absorbed from the diet. Vitamin D undergoes enzymatic conversion to its active form, 1,25-dihydroxyvitamin D (1,25D), a ligand to the nuclear vitamin D receptor (VDR), which activates target gene expression. The best-known role of 1,25D is to maintain healthy bones by increasing the intestinal absorption and renal reuptake of calcium. Besides bone maintenance, 1,25D has many other functions, such as the inhibition of cell proliferation, induction of cell differentiation, augmentation of innate immune functions, and reduction of inflammation. Significant amounts of data regarding the role of vitamin D, its metabolism and VDR have been provided by research performed using mice. Despite the fact that humans and mice share many similarities in their genomes, anatomy and physiology, there are also differences between these species. In particular, there are differences in composition and regulation of the VDR gene and its expression, which is discussed in this article.

Vitamin D

1999 ◽  
Vol 277 (2) ◽  
pp. F157-F175 ◽  
Author(s):  
Alex J. Brown ◽  
Adriana Dusso ◽  
Eduardo Slatopolsky
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Critical Role ◽  
Active Form ◽  
Cell Surface Receptor ◽  
Dihydroxyvitamin D ◽  
Surface Receptor ◽  
A Cell ◽  
Second Messenger Pathways

The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], binds with high affinity to a specific cellular receptor that acts as a ligand-activated transcription factor. The activated vitamin D receptor (VDR) dimerizes with another nuclear receptor, the retinoid X receptor (RXR), and the heterodimer binds to specific DNA motifs (vitamin D response elements, VDREs) in the promoter region of target genes. This heterodimer recruits nuclear coactivators and components of the transcriptional preinitiation complex to alter the rate of gene transcription. 1,25(OH)2D3also binds to a cell-surface receptor that mediates the activation of second messenger pathways, some of which may modulate the activity of the VDR. Recent studies with VDR-ablated mice confirm that the most critical role of 1,25(OH)2D3is the activation of genes that control intestinal calcium transport. However, 1,25(OH)2D3can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)2D3and its analogs.

Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.

2002 ◽  
pp. 45-59 ◽  
Author(s):  
K W Colston ◽  
C M√∏rk Hansen
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Bone Mineralization ◽  
Active Form ◽  
Cell Types ◽  
Cell Cycle Regulators ◽  
Dihydroxyvitamin D ◽  
Cell Growth And Differentiation ◽  
Regulatory Effects ◽  
Apoptotic Effects

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

scholarly journals Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

2016 ◽  
Vol 37 (5) ◽  
pp. 521-547 ◽  
Author(s):  
Peter J. Tebben ◽  
Ravinder J. Singh ◽  
Rajiv Kumar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Elevated Serum ◽  
Diagnosis And Treatment ◽  
Vitamin D Metabolites ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

Vitamin D

2005 ◽  
Vol 289 (1) ◽  
pp. F8-F28 ◽  
Author(s):  
Adriana S. Dusso ◽  
Alex J. Brown ◽  
Eduardo Slatopolsky
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Endocrine System ◽  
Target Cells ◽  
Vitamin D Metabolism ◽  
Diverse Range ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Single Receptor ◽  
Recent Developments

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.

scholarly journals Back to the future: a new look at ‘old’ vitamin D

2008 ◽  
Vol 198 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Rene F Chun ◽  
John S Adams ◽  
Martin Hewison
Keyword(s):  
Vitamin D ◽  
Vitamin D Insufficiency ◽  
Target Cells ◽  
Bone Homeostasis ◽  
Immune Disorders ◽  
Factors Associated ◽  
Dihydroxyvitamin D ◽  
High Prevalence ◽  
Fresh Perspective ◽  
Vitamin D Signaling

Our perception of the vitamin D system continues to evolve. Recent studies have re-evaluated the parameters for adequate vitamin D status in humans, revealing a high prevalence of insufficiency in many populations throughout the world. Other reports have highlighted the potential consequences of vitamin D insufficiency beyond established effects on bone homeostasis. Most notably, there is now strong evidence of a role for vitamin D in modulating innate and adaptive immunities, with insufficiency being linked to infectious disease and other immune disorders. To date, signaling pathways for these new responses to vitamin D have been based on established endocrine models for active 1,25-dihydroxyvitamin D, despite present evidence for more localized, intracrine modes of action. In the following review, we provide a fresh perspective on vitamin D signaling in non-classical target cells such as macrophages by highlighting novel factors associated with the transport and action of this pluripotent secosteroid.

scholarly journals The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
James P. Whitcomb ◽  
Mary DeAgostino ◽  
Mark Ballentine ◽  
Jun Fu ◽  
Martin Tenniswood ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Vitamin D Receptor ◽  
Leishmania Major ◽  
Active Form ◽  
Wild Type ◽  
Vitamin D Signaling ◽  
Deficient Mice ◽  
Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

scholarly journals Vitamin D and Endometrium: A Systematic Review of a Neglected Area of Research

2018 ◽  
Vol 19 (8) ◽  
pp. 2320 ◽  
Author(s):  
Greta Cermisoni ◽  
Alessandra Alteri ◽  
Laura Corti ◽  
Elisa Rabellotti ◽  
Enrico Papaleo ◽  
...  
Keyword(s):  
Vitamin D ◽  
Endometrial Cancer ◽  
Inflammatory Responses ◽  
Active Form ◽  
Molecular Data ◽  
Secretory Phase ◽  
Endometrial Cells ◽  
Mrna And Protein Expression ◽  
Anti Inflammatory

Growing evidence supports a role of vitamin D (VD) in reproductive health. Vitamin D receptor (VDR) is expressed in the ovary, endometrium, and myometrium. The biological actions of VD in fertility and reproductive tissues have been investigated but mainly using animal models. Conversely, the molecular data addressing the mechanisms underlying VD action in the physiologic endometrium and in endometrial pathologies are still scant. Levels of VDR expression according to the menstrual cycle are yet to be definitively clarified, possibly being lower in the proliferative compared to the secretory phase and in mid-secretory compared to early secretory phase. Endometrial tissue also expresses the enzymes involved in the metabolism of VD. The potential anti-proliferative and anti-inflammatory effects of VD for the treatment of endometriosis have been investigated in recent years. Treatment of ectopic endometrial cells with 1,25(OH)2D3 could significantly reduce cytokine-mediated inflammatory responses. An alteration of VD metabolism in terms of increased 24-hydroxylase mRNA and protein expression has been demonstrated in endometrial cancer, albeit not consistently. The effect of the active form of the vitamin as an anti-proliferative, pro-apoptotic, anti-inflammatory, and differentiation-inducing agent has been demonstrated in various endometrial cancer cell lines.

scholarly journals The Role of the Intraplaque Vitamin D System in Atherogenesis

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Federico Carbone ◽  
Fabrizio Montecucco
Keyword(s):  
Vitamin D ◽  
Clinical Findings ◽  
Peripheral Tissues ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Mouse Tissues ◽  
Calcium Phosphorus ◽  
25 Hydroxyvitamin D ◽  
Physiological Pathways

Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed.

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