From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health.

New knowledge of the biological and clinical importance of the steroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and its receptor, the vitamin D receptor (VDR), has resulted in significant contributions to good bone health. However, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clinical knowledge is not being translated into better human health. Over the past several decades, the biological sphere of influence of vitamin D(3), as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis (intestine, bone, kidney, and parathyroid). Now, research has shown that the pluripotent steroid hormone 1alpha,25(OH)(2)D(3) initiates the physiologic responses of >/=36 cell types that possess the VDR. In addition to the kidney's endocrine production of circulating 1alpha,25(OH)(2)D(3,) researchers have found a paracrine production of this steroid hormone in >/=10 extrarenal organs. This article identifies the fundamentals of the vitamin D endocrine system, including its potential for contributions to good health in 5 physiologic arenas in which investigators have clearly documented new biological actions of 1alpha,25(OH)(2)D(3) through the VDR. As a consequence, the nutritional guidelines for vitamin D(3) intake (defined by serum hydroxyvitamin D(3) concentrations) should be reevaluated, taking into account the contributions to good health that all 36 VDR target organs can provide.

[1]  A. Need.  Bone resorption markers in vitamin D insufficiency. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[2]  F. Wrba,et al.  25-Hydroxyvitamin D3-1α-hydroxylase Expression in Normal and Malignant Human Colon , 2004, Journal of Histochemistry and Cytochemistry.

[3]  S. Manolagas,et al.  1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. , 1984, Science.

[4]  P. Lips,et al.  13th Workshop consensus for vitamin D nutritional guidelines , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[5]  B. Taylor,et al.  Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a consensus statement , 2006, The Medical journal of Australia.

[6]  M. Campbell,et al.  Biological actions of extra-renal 25-hydroxyvitamin D-1α-hydroxylase and implications for chemoprevention and treatment , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[7]  B. Hollis,et al.  Vitamin D2 is much less effective than vitamin D3 in humans. , 2004, The Journal of clinical endocrinology and metabolism.

[8]  A. Mackay-Sim,et al.  Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle , 2004, Physiology & Behavior.

[9]  G. Åkerström,et al.  25-hydroxyvitamin D3-1α-hydroxylase expression in normal and pathological parathyroid glands , 2002 .

[10]  J. Kanis,et al.  Effects of 24,25-dihydroxy-vitamin D3 on its plasma level in man. , 1981, Metabolic bone disease & related research.

[11]  S. Manolagas,et al.  1,25-dihydroxyvitamin D3 receptors in human leukocytes. , 1983, Science.

[12]  H. M. Wehr,et al.  Reverse phase liquid chromatographic determination of vitamins D2 and D3 in milk. , 1982, Journal - Association of Official Analytical Chemists.

[13]  D. Feldman,et al.  Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  Anthony W. Norman,et al.  Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model , 2004, Nature Reviews Drug Discovery.

[15]  J. Ellard.  Where We are, and Where We are Going , 1988, The Australian and New Zealand journal of psychiatry.

[16]  N. Bayley,et al.  Failure , 1890, The Hospital.

[17]  R. Larkins,et al.  VITAMIN D METABOLISM , 1977, The Medical journal of Australia.

[18]  E. Jacobs,et al.  Nuclear Vitamin D Receptor: Structure-Function, Molecular Control of Gene Transcription, and Novel Bioactions , 2005 .

[19]  A. Norman,et al.  Profile of ligand specificity of the vitamin D binding protein for 1α,25‐dihydroxyvitamin d3 and its analogs , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  A. Norman,et al.  Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. , 1981, The New England journal of medicine.

[21]  A. Norman,et al.  The Vitamin D Receptor Is Present in Caveolae-Enriched Plasma Membranes and Binds 1α,25(OH)2-Vitamin D3 in Vivo and in Vitro , 2004 .

[22]  H. Nordgren,et al.  25-Hydroxyvitamin D3 1α-hydroxylase expression in breast cancer and use of non-1α-hydroxylated vitamin D analogue , 2005, Breast Cancer Research.

[23]  R. Simpson,et al.  Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[24]  Barbara A Gilchrest,et al.  The vitamin D questions: how much do you need and how should you get it? , 2006, Journal of the American Academy of Dermatology.

[25]  John H. White,et al.  Cutting Edge: 1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression1 , 2004, The Journal of Immunology.

[26]  R. Vieth,et al.  Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. , 1998, The American journal of clinical nutrition.

[27]  M. Uskoković,et al.  Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[28]  K. Badenhoop,et al.  Vitamin D and type 1 diabetes mellitus: state of the art , 2005, Trends in Endocrinology & Metabolism.

[29]  B. May,et al.  The 25-Hydroxyvitamin D 24-Hydroxylase , 1997 .

[30]  M. Holick.  High prevalence of vitamin D inadequacy and implications for health. , 2006, Mayo Clinic proceedings.

[31]  M. Campbell,et al.  Mechanisms of decreased Vitamin D 1α-hydroxylase activity in prostate cancer cells , 2004, Molecular and Cellular Endocrinology.

[32]  E. D. Barnhart.  Physicians Desk Reference , 1990 .

[33]  A. Norman,et al.  Minireview: vitamin D receptor: new assignments for an already busy receptor. , 2006, Endocrinology.

[34]  T. Shinki,et al.  Vitamin D and bone , 2003, Journal of cellular biochemistry.

[35]  Shu Q. Liu,et al.  1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system , 2002 .

[36]  B. Hollis,et al.  The assessment of circulating 25(OH)D and 1,25(OH)2D: Where we are and where we are going , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[37]  A. Norman,et al.  Rapid modulation of osteoblast ion channel responses by 1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Y. Helfrich,et al.  Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. , 2007, The Journal of clinical investigation.

[39]  E. Kallay,et al.  Regulation of extrarenal synthesis of 1,25-dihydroxyvitamin D3--relevance for colonic cancer prevention and therapy. , 2003, Molecular aspects of medicine.

[40]  E. V. Mccollum,et al.  STUDIES ON EXPERIMENTAL RICKETS. , 2009 .

[41]  L. Mosekilde,et al.  Serum levels of vitamin D metabolites and bone remodelling in hyperthyroidism. , 1982, Metabolism: clinical and experimental.

[42]  P. Elias,et al.  25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. , 2004, The Journal of investigative dermatology.

[43]  Ming,et al.  Synthesis of 1 α, 25-Dihydroxyvitamin D3 , 2003 .

[44]  B. Boucher,et al.  Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. , 2004, The American journal of clinical nutrition.

[45]  M. Burch,et al.  Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure , 2007, Heart.

[46]  C. Mathieu,et al.  Mechanism and potential of the growth-inhibitory actions of vitamin D and ana-logs. , 2007, Current medicinal chemistry.

[47]  H. Goldblatt,et al.  A Study of Rats on a Normal Diet Irradiated daily by the Mercury Vapour Quartz Lamp or kept in Darkness. , 1923, The Biochemical journal.

[48]  Steven A. Smith,et al.  Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. , 2005, Journal of chemical neuroanatomy.

[49]  C. Weaver,et al.  Vitamin D requirements: current and future. , 2004, The American journal of clinical nutrition.

[50]  A. Norman,et al.  Presence of a truncated form of the vitamin D receptor (VDR) in a strain of VDR-knockout mice. , 2005, Endocrinology.

[51]  E. V. Mccollum,et al.  STUDIES ON EXPERIMENTAL RICKETS XXI. AN EXPERIMENTAL DEMONSTRATION OF THE EXISTENCE OF A VITAMIN WHICH PROMOTES CALCIUM DEPOSITION , 1922 .

[52]  C. Mathieu,et al.  Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice , 2004, Diabetologia.

[53]  A. Norman,et al.  Vitamin D: A Cholecalciferol Metabolite Highly Active in Promoting Intestinal Calcium Transport , 1971, Science.

[54]  M. Saad,et al.  Hypovitaminosis D is associated with insulin resistance and β cell dysfunction , 2004 .

[55]  A. Saenger,et al.  Quantification of serum 25-hydroxyvitamin D(2) and D(3) using HPLC-tandem mass spectrometry and examination of reference intervals for diagnosis of vitamin D deficiency. , 2006, American journal of clinical pathology.

[56]  B. Gilchrest.  Sun protection and Vitamin D: Three dimensions of obfuscation , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[57]  M. Boyle,et al.  Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis. , 2005, American journal of respiratory and critical care medicine.

[58]  C. Mathieu,et al.  Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[59]  W. Willett,et al.  The urgent need to recommend an intake of vitamin D that is effective. , 2007, The American journal of clinical nutrition.

[60]  G. Åkerström,et al.  25-hydroxyvitamin D(3)-1alpha-hydroxylase expression in normal and pathological parathyroid glands. , 2002, The Journal of clinical endocrinology and metabolism.

[61]  R. Bouillon,et al.  Structure-function relationships in the vitamin D endocrine system. , 1995, Endocrine reviews.

[62]  M. Kilby,et al.  Vitamin D and Placental-Decidual Function , 2004, The Journal of the Society for Gynecologic Investigation: JSGI.

[63]  P. Holst.  Experimental Rickets , 1927, Epidemiology and Infection.

[64]  F. Glorieux,et al.  The 25‐Hydroxyvitamin D 1‐Alpha‐Hydroxylase Gene Maps to the Pseudovitamin D‐Deficiency Rickets (PDDR) Disease Locus , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[65]  M. Drezner,et al.  HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. , 2006, Clinical chemistry.

[66]  W. O'Fallon,et al.  Relationship of intestinal calcium absorption to 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in young versus elderly women: evidence for age-related intestinal resistance to 1,25(OH)2D action. , 2000, The Journal of clinical endocrinology and metabolism.

[67]  G. Grodsky,et al.  Vitamin D deficiency inhibits pancreatic secretion of insulin. , 1980, Science.

[68]  M. Drezner,et al.  Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[69]  R. Nicolaysen.  Studies upon the mode of action of vitamin D: The absorption of calcium chloride, xylose and sodium sulphate from isolated loops of the small intestine and of calcium chloride from the abdominal cavity in the rat. , 1937, The Biochemical journal.

[70]  H. Pols,et al.  Vitamin D , 1928, Calcified Tissue International.

[71]  J. Rhim,et al.  Targeted Disruption of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene in ras-Transformed Keratinocytes Demonstrates That Locally Produced 1α,25-Dihydroxyvitamin D3 Suppresses Growth and Induces Differentiation in an Autocrine Fashion11 Canadian Institutes of Health Research Grant MT10839 (to R.K.). , 2002 .

[72]  C. Carlberg.  Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. , 2003, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[73]  C. Wagner,et al.  Normal serum vitamin D levels. , 2005, The New England journal of medicine.

[74]  S. Massry,et al.  1,25 Dihydroxy-vitamin D3 in normal man and patients with renal failure. , 1974, Annals of internal medicine.

[75]  J. McGrath,et al.  Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain , 2005, Journal of Chemical Neuroanatomy.

[76]  A. Norman,et al.  Action of 1,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D, in uremic man. , 1972, The New England journal of medicine.

[77]  J. Rhim,et al.  Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in ras-transformed keratinocytes demonstrates that locally produced 1alpha,25-dihydroxyvitamin D3 suppresses growth and induces differentiation in an autocrine fashion. , 2002, Molecular cancer research : MCR.

[78]  S. Woodman,et al.  Caveolae: From Cell Biology to Animal Physiology , 2002, Pharmacological Reviews.

[79]  A. Norman,et al.  Demonstration that the Vitamin D Metabolite 1,25(OH)2-Vitamin D3 and Not 24R,25(OH)2-Vitamin D3 Is Essential for Normal Insulin Secretion in the Perfused Rat Pancreas , 1985, Diabetes.

[80]  A. Mackay-Sim,et al.  Developmental vitamin D deficiency alters adult behaviour in 129/SvJ and C57BL/6J mice , 2008, Behavioural Brain Research.

[81]  Joseph L. Napoli,et al.  Vitamin D Metabolism , 1984 .

[82]  R. Nicolaysen,et al.  Studies upon the mode of action of vitamin D: The influence of vitamin D on the absorption of calcium and phosphorus in the rat. , 1937, The Biochemical journal.