Vitamin D: Physiology, Molecular Biology, and Clinical Applications (Nutrition and Health) Michael F. Holick (Editor) April 2010
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Adriana S. Dusso1 and Masanori Tokumoto1
(1) Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
The kidney is essential for the integrity of the vitamin D endocrine system: Normal kidney function ensures adequate serum levels of 1,25-dihyrdroxyvitamin D (1,25(OH)2D, the hormonal form of vitamin D) and of its precursor, 25-hydroxyvitamin D 25(OH)D. In turn, normal serum 1,25(OH)2D and 25(OH)D levels are critical in maintaining normal kidney function and in ameliorating the progression of kidney disease. Research in the last three decades has firmly established that renal conversion of 25(OH)D to 1,25(OH)2D plays a key role in the maintenance of calcium and phosphate homeostasis and skeletal health. 1,25(OH)2D endocrine actions include the coordinated regulation of the synthesis of parathyroid hormone (PTH), the bone phosphatonin FGF23, and its own serum concentrations, and consequently of the hormonal loops and ion fluxes between the parathyroid gland, the intestine, the kidney, and the bone. 1,25(OH)2D tight control of this multi-organ endocrine system is central not only for bone integrity but also in preventing an excess of serum calcium and phosphate predisposing to over-mineralization of bone or ectopic calcification. Importantly, recent epidemiological evidence also suggests that the kidney is essential for the maintenance of normal serum 25(OH)D levels, a requirement for 1,25(OH)2D autocrine actions. Renal uptake of 25(OH)D from the glomerular ultrafiltrate is an active process necessary for both renal and extrarenal 1,25(OH)2D production. Normal renal uptake of 25(OH)D ensures the appropriate delivery of 25(OH)D for its conversion to 1,25(OH)2D by an increasing number of nonrenal cells. Autocrine 1,25(OH)2D actions in 1,25(OH)2D producing cells, which include parathyroid cells, osteoblasts, and cells of the immune and cardiovascular system, appear to mediate the multiple health benefits and the survival advantage conferred to the general population by a normal vitamin D status. This chapter presents the current understanding of the mechanisms mediating renal control of vitamin D metabolism and 1,25(OH)2D endocrine and autocrine actions important in disease prevention, with a special focus on the renoprotective actions of the vitamin D endocrine system that prevent/ameliorate the onset and progression of kidney disease.
Molecular Defects in the Vitamin D Receptor Associated with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR)
Peter J. Malloy1 and David Feldman1
Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford University Medical Center, Stanford, CA 94305-5103, USA
Vitamin D is important in skeletal development and in bone mineralization. The active form of vitamin D, 1?,25-dihydroxyvitamin D, 1,25(OH)2D, binds with high affinity to the vitamin D receptor (VDR), a member of the nuclear receptor family of transcription factors. Genetic mutations in the vitamin D receptor cause the rare genetic disease hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR). Children with HVDRR have rickets, hypocalcemia, hypophosphatemia, and secondary hyperparathyroidism. Some have total alopecia. A number of heterogeneous mutations have been identified in the VDR as the molecular cause of HVDRR. Mutations in DNA-binding domain inactivate the VDR by disrupting contact with VDREs in promoters of target genes. Mutations in the ligand-binding domain reduce the affinity of the VDR for 1,25(OH)2D, prevent the 1,25(OH)2D from binding to the VDR, inhibit RXR heterodimerization, or abolish coactivator interactions. Other types of mutations have also been found including nonsense mutations, splice site mutations, deletions, insertions, and duplications. Children with HVDRR have been successfully treated with intravenous calcium that bypasses the intestinal defect in calcium transport due to the lack of 1,25(OH)2D action on the mutant VDR.
Johan Moan1, 2 Contact Information, Øyvind Sverre Bruland3, Arne Dahlback2, Asta Juzeniene1 and Alina Carmen Porojnicu1
(1) Department of Radiation Biology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, 0310 Oslo, Norway
(2) Department of Physics, University of Oslo, Oslo, 0316, Norway
(3) Department of Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, 0310 Oslo, Norway
Vitamin D plays an important role in cancer prevention and prognosis. A good vitamin D status at the time of diagnosis and therapy start seems to improve survival. Due to the sun, the serum concentration of 25-hydroxyvitamin D 25(OH)D is higher in summer than in winter. The vitamin D status in Norway and its impact on cancer prognosis was reviewed: 137,706 cases of breast, colon and prostate cancer and Hodgkin’s lymphoma were analysed with respect to survival 3 years after diagnosis. The survival rates for these cancer forms were about 20% higher for summer diagnosis than for winter diagnosis. The effect was largest for the youngest patients. The concentration of 25(OH)D in serum was 49 ± 2 nmol/l in the winter and 66 ± 5 nmol/l in the summer, while the level of 1,25-dihydroxyvitamin D 1,25(OH)2D remained almost constant during the year, except for persons with high body mass index, for whom there was a similar seasonal variation as for 25(OH)D. It seems that 25(OH)D, rather than 1,25(OH)2D, may be the main metabolite influencing cancer survival. Vitamin D supplementation or, alternatively, exposure to ultraviolet radiation may be considered as adjuvants in cancer therapy.
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Reinhold Vieth1 Contact Information
(1) Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, Toronto, ON, M5G 1X5, Canada
There remains great concern by the medical community about the potential toxicity of vitamin D. Vitamin D intoxication is associated with hypercalciuria, hypercalcemia and hyperphosphatemia which causes soft tissue calcification of the kidneys and blood vessels and increases the risk of kidney stones. The hallmark for vitamin D intoxication is a markedly elevated blood level of 25-hydroxyvitamin D that is usually greater than 150–200 ng/mL. The Institute of Medicine’s Food and Nutrition Board recommended the upper limit (UL) to be 2000 IU of vitamin D a day. However dose ranging studies in healthy adults revealed that 10,000 IU of vitamin D a day for five months did not cause any toxicity on calcium metabolism. In a separate study up to 40,000 IU of vitamin D a day for one month did not affect calcium metabolism. Therefore it is reasonable to increase the upper limit for vitamin D to at least 10,000 IU/day. Because the production of vitamin D in the skin is controlled by sunlight there is no concern about making too much of vitamin D from excessive exposure to sunlight. Therefore vitamin D is very safe and has a wide therapeutic index.
Carsten Carlberg1, 2 Contact Information
(1) Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg
(2) Department of Biochemistry, University of Kuopio, FIN-70211 Kuopio, Finland
The vitamin D receptor (VDR) is a ligand-inducible transcription factor, whose target genes play key roles in cellular metabolism, bone formation, cellular growth, differentiation, and in controlling inflammation. Many of these VDR target genes are also involved in dysregulated pathways leading to common human diseases, such as cancer, osteoporosis, or the metabolic syndrome. The activation of VDR by natural and synthetic ligands may improve such pathological conditions. On a genomic level these pathways converge on regulatory modules, some of which contain VDR-binding sites, so-called vitamin D response elements (VDREs). Transcriptome analysis, chromatin immunoprecipitation scans and in silico screening approaches already identified many genomic targets of the VDR. Important regulatory modules with VDREs should have a major impact on understanding the role and potential therapeutic value of VDR and its ligands.
John S. Adams1 Contact Information, Hong Chen2, Thomas S. Lisse2, Rene F. Chun2 and Martin Hewison1
(1) Department of Orthopaedic Surgery, University of California at Los Angeles, Los Angeles, CA, USA
(2) Department of Orthopedic Surgery and Department of Molecular, Cell and Developmental Biology, Orthopedic Hospital Research Center, UCLA/Orthopedic Hospital UCLA, Los Angeles, CA 90095-7358, USA
Learning from Nature. Experiments of nature are crucial for informing scientific discovery. Twenty five years ago we began to investigate an outbreak of rachitic bone disease in adolescent, female New World primates residing at the Los Angles Zoo. Our investigation of this “experiment of nature” and that of an adolescent human female with a similar phenotype (Chen et al., Proc Natl Acad Sci USA 100:6109–6114, 2003) led us to the discovery of a novel means for relative resistance to vitamin D and estrogen in primates, including man. We coined these resistance-causing proteins as the vitamin D response element-binding protein (VDRE-BP) and estrogen response element-binding protien (ERE-BP) for their ability to compete in trans with the liganded vitamin D receptor and estrogen receptor ? for their cognate response elements, identifying them as nucleic acid-binding proteins in the heterogeneous nuclear ribonucleoprotein C family (Chen et al., J Biol Chem 275:35557–35564, 2000; J Clin Invest 99:769–775, 1997). The purpose of this review is to examine the role of one of these proteins, the VDRE-BP, and other associated intracellular proteins that regulate the expression of vitamin D-controlled genes in nonhuman and human primates.
Mona S. Calvo1 Contact Information and Susan J. Whiting2
(1) Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, USA
(2) College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
The objective of our chapter is to provide convincing evidence of how changes in food consumption patterns, judicious fortification of food staples, and targeted supplementation of at-risk groups could be effective public health strategies to help increase vitamin D intake, maintain bone health, and potentially prevent chronic disease. We demonstrate the limitations of the Canadian and American food supply to provide sufficient vitamin D to meet increased dietary needs when cutaneous synthesis of vitamin D is compromised. Vitamin D deficiency as measured by low circulating 25-hydroxyvitamin D 25(OH)D and its link to increased risk of chronic disease is a significant global reality and threat to general public health, yet dietary intakes of vitamin D remain lower than the recommended dietary guidelines for the majority of individuals experiencing the lowest levels of 25(OH)D.
(1) MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, WC1N 1EH, UK
Type 1 diabetes is an autoimmune disease resulting from a progressive destruction of the insulin-secreting ?-cells. There is no cure or preventive treatment for type 1 diabetes. However, increased vitamin D intake is currently considered as one of the most promising candidates for prevention. The biological mechanisms for a role of vitamin D in diabetes development are plausible and as reviewed in this chapter, evidence to support an association has been obtained from various lines of investigation.
Gary G. Schwartz1
(1) Departments of Cancer Biology and Epidemiology and Prevention, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, USA
The hypothesis that vitamin D deficiency increases risk the for clinical prostate cancer has stimulated a large body of epidemiologic research including observational studies of sunlight exposure, serum vitamin D metabolites, and polymorphisms in the vitamin D receptor. The many studies on sunlight exposure strongly support a protective role for sunlight exposure. Conversely, the data from serological studies are mixed. Paradoxically, two studies suggest that high vitamin D levels may be associated with increased risk. Our recent demonstration that serum levels of calcium are strongly and positively related to prostate cancer risk may help resolve this discrepancy as high levels of vitamin D may be associated with normal, but relatively high values for serum calcium. These data indicate that elements of the vitamin D endocrine system whose investigation previously has attracted little attention, i.e., serum calcium and parathyroid hormone, are likely to exert important effects on the natural history of prostate cancer.
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Martin A. Montecino1 Jane B. Lian2, Janet L. Stein2, Gary S. Stein2, André J. van Wijnen2 and Fernando Cruzat1
(1) Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias Biologicas, Universidad de Concepcion, Concepcion, Chile
(2) Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
The physiological activities of 1,25-dihydroxyvitamin D3 1,25(OH)2D, the active hormone of vitamin D3, in the skeleton are far-reaching and include development and turnover of bone, differentiation and survival of distinct bone cell populations, and maintaining calcium and bone homeostasis through positive and negative control of gene expression. Here we describe these functional activities within the context of the molecular mechanisms established for the bone tissue-specific osteocalcin gene, involving interactions of the vitamin D receptor transcriptional complexes that contribute to various 1,25(OH)2D activities in the skeleton.
Role of Vitamin D and Vitamin D Analogs for Bone Health and Survival in Chronic Kidney Disease pages 955-965
Ishir Bhan1 Contact Information, Hector Tamez1 and Ravi Thadhani1
(1) Renal Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Chronic kidney disease (CKD) is accompanied by reduced conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and is often also associated with a deficiency of 25-hydroxyvitamin D. These and other metabolic changes can lead to secondary hyperparathyroidism and a range of disorders of bone turnover, mineralization, and volume, the most prominent of which is osteitis fibrosa cystica. Attempts to prevent this disorder have led to widespread use of vitamin D receptor agonists, but may increase the risk of adynamic bone disease. Beyond its use in regulating bone metabolism, several studies suggest that vitamin D may influence survival in advanced CKD. Potential mechanisms for this effect are likely to influence cardiovascular disease, the leading cause of death in CKD. Alterations in left ventricular function and the renin–angiotensin–aldosterone axis appear to be modulated by vitamin D. We discuss these and other aspects of the role vitamin D may play in the CKD population as well as the current state of evidence supporting therapeutic use.
David A. Hanley1
(1) Departments of Medicine, Community Health Sciences and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
Vitamin D deficiency is common in Canada, but the prevalence depends on how deficiency is defined. With the increasing use of serum 25-OH cholecalciferol measurements, the extent of the problem is being uncovered. If the lower limit of the optimal range for this vitamin D metabolite is regarded as the threshold for vitamin D deficiency, then the majority of Canadians are deficient for at least part of the year. Rickets is still a recognized problem for Canadian children, particularly in breast-fed infants of vitamin D-deficient mothers. Individuals at particularly high risk for vitamin D deficiency in Canada are aboriginal peoples and ambulant or institutionalized elderly individuals.
Linda A. Merlino1
(1) The University of Iowa, Iowa city, IA, USA
Rheumatoid arthritis is an autoimmune disease that causes pain, swelling, and deformity of the joints and may result in other systemic effects. In animal models, vitamin D has been shown to suppress autoimmunity; however, in humans the role of vitamin D is less clear as to the effects on rheumatoid arthritis. There do appear to be suppressive effects of specific disease mechanisms; however, epidemiologic results on the effect of vitamin D on the development of the disease are contradictory. A better understanding of the rheumatoid arthritis immune system and the effects of vitamin D is needed before conclusions can be drawn.
(1) Department of Endocrinology and Metabolism C, Aarhus University Hospital, DK 8000 rhus C, Denmark
Deficiency and insufficiency is common in the Northern, Western, and Central part of Europe. Around 43–92% of adults and 89–97% of teenage girls have plasma 25-hydroxyvitamin D 25(OH)D levels < 50 nmol/l. The vitamin D deficiency is caused by low sun exposure especially during winter time and because of the high latitudes in the Northern regions. The lack of solar exposure is combined with a low dietary vitamin D intake especially in the Central and Western part of the continent. The high dietary intake of fatty fish, cod liver, and cod liver oil in Scandinavia and Iceland and the frequent use of supplements mitigate to some extent the effect of the reduced sun exposure. Across Europe, epidemiologic studies indicate a positive effect of latitude on average plasma levels of 25(OH)D. However, at the level of the individual country (e.g., France and the United Kingdom) with a more common fortification policy and supplementation tradition, latitude is inversely related to plasma 25(OH)D. At the individual level, European studies have confirmed that plasma 25(OH)D depends positively on dietary vitamin D, vitamin D supplementation, sun exposure, living in partnership, recent vacations to sunny regions, and sunbed use and inversely on use of sunscreen and covering clothes, smoking habits, and body mass index. Risk groups include breast-fed children, pregnant and lactating women, and older persons. Veiled and pigmented immigrant women with covering clothes and vegetarians constitute a special problem. Vitamin D status can be improved by encouraging safe sun exposure, improving dietary intake, e.g., by fish and cod liver oil, obligatory food fortification, and vitamin D supplements. Nutritional recommendations from governments and other regulatory institutions should be adapted to the present knowledge of the actual need of vitamin D.
Diane R. Dowd1 and Paul N. MacDonald1
(1) Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
The biological effects of 1,25-dihydroxyvitamin D3 1,25(OH)2D are mediated through a soluble receptor protein termed the vitamin D receptor (VDR). The VDR binds 1,25(OH)2D with high affinity and high selectivity. In the target cell, the interaction of the 1,25(OH)2D hormone with VDR initiates a complex cascade of molecular events culminating in alterations in the rate of transcription of specific genes or gene networks. This chapter discusses the molecular biology of the VDR and focuses on various aspects of VDR function with an emphasis on the macromolecular interactions that are required for the transcriptional regulatory activity of the VDR. These macromolecular interactions include the association of VDR with the 1,25(OH)2D ligand, the mechanisms required for specific, high-affinity interaction of VDR with DNA, the heterodimeric interaction of VDR with retinoid X receptor (RXR), and protein–protein contacts that comprise the communication links between the VDR and the transcriptional machinery. This chapter also touches on some recent data that suggest that the VDR has transcriptional activity independent of the 1,25(OH)2D ligand in the hair follicle and in the skin. This last aspect demonstrates a novel role for the VDR and its implications in the transcriptional mechanism of the VDR are profound.
Edward Giovannucci , 777-795,
The relation between vitamin D status and cancer risk has been investigated in a number of epidemiologic studies, while data from interventional studies remain scarce. The approaches to estimate vitamin D status have been varied and include direct measures of circulating 25-hydroxyvitamin D 25(OH)D levels, surrogates or determinants of 25(OH)D, including region of residence, intake, and sun exposure estimates. In terms of cancer sites, the body of evidence is most extensive for colorectal cancer, for which support comes from studies of 25(OH)D, vitamin D intake, multiple predictors of 25(OH)D, and region of residence in a sunny climate. The evidence for breast cancer is also intriguing but prospective studies of 25(OH)D are sparse and somewhat conflicting. In one case–control study, retrospectively reported sun exposure during ages 10–19 was most strongly associated with reduced risk of breast cancer. For prostate cancer, the data on circulating 25(OH)D have been equivocal, suggesting no association or a weak inverse association, but studies tend to support a benefit of sun exposure on prostate cancer risk. It is plausible that for prostate cancer, vitamin D level much longer before the time of diagnosis is the most relevant exposure. Most of the epidemiologic studies to date have examined vitamin D status in relation to risk of cancer, but emerging evidence suggests that vitamin D may be an important factor for cancer progression and mortality, independently of any effects on incidence. Further study is needed to establish the precise role of vitamin D on carcinogenesis, especially in terms of when in the life span and on what stages of carcinogenesis vitamin D is relevant, the precise intakes and levels required, the magnitude of the association, and which cancer sites are most affected.
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