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Vitamin D3; the sunshine vitamin

The vitamin D deficiency pandemic and consequences for nonskeletal health: Mechanisms of action.

Holick MF. Mol Aspects Med. 2008 Sep 2. Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, MA, United States.

Vitamin D, the sunshine vitamin, is important for childhood bone health. Over the past two decades, it is now recognized that vitamin D not only is important for calcium metabolism and maintenance of bone health throughout life, but also plays an important role in reducing risk of many chronic diseases including type I diabetes, multiple sclerosis, rheumatoid arthritis, deadly cancers, heart disease and infectious diseases.

How vitamin D is able to play such an important role in health is based on observation that all tissues and cells in the body have a vitamin D receptor, and, thus, respond to its active form 1,25-dihydroxyvitamin D. However, this did not explain how living at higher latitudes and being at risk of vitamin D deficiency increased risk of these deadly diseases since it was also known that the 1,25-dihydroxyvitamin D levels are normal or even elevated when a person is vitamin D insufficient. Moreover, increased intake of vitamin D or exposure to more sunlight will not induce the kidneys to produce more 1,25-dihydroxyvitamin D. The revelation that the colon, breast, prostate, macrophages and skin among other organs have the enzymatic machinery to produce 1,25-dihydroxyvitamin D provides further insight as to how vitamin D plays such an essential role for overall health and well being. This review will put into perspective many of the new biologic actions of vitamin D and on how 1,25-dihydroxyvitamin D is able to regulate directly or indirectly more than 200 different genes that are responsible for a wide variety of biologic processes.

Vitamin D in health and disease.

Heaney RP. Clin J Am Soc Nephrol. 2008 Sep;3(5):1535-41. Epub 2008 Jun 4.
Creighton University, Omaha, NE 68131, USA. rheaney@creighton.edu

Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D(3)) is substantially more potent than ergocalciferol (vitamin D(2)) and that the safe upper intake level for vitamin D(3) is 10,000 IU/d. (= 250µg)

Vitamin D and living in northern latitudes--an endemic risk area for vitamin D deficiency.

Huotari A, Herzig KH. Int J Circumpolar Health. 2008 Jun;67(2-3):164-78
A I Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.

OBJECTIVES: To review the current literature on the health effects of vitamin D, especially the effects on inhabitants living in the northern latitudes.

STUDY DESIGN: Literature review.

METHODS: The scientific literature concerning health effects of vitamin D was reviewed and the current dietary recommendations for inhabitants living in northern latitudes were discussed.

RESULTS: Vitamin D is a steroid-structured hormone produced in the skin upon exposure to UVB-radiation or obtained from certain food products (for example, liver). Its production is mediated by the vitamin D receptor, which belongs to the nuclear receptor family, and exerts its function as a transcription factor regulating several target genes. Active metabolites of vitamin D play an important role in calcium and phosphate homeostasis. Deficiency of vitamin D results in diminished bone mineralization and an increased risk of fractures. In addition, vitamin D is connected to a variety of other diseases that include different cancer types, muscular weakness, hypertension, autoimmune diseases, multiple sclerosis, type 1 diabetes, schizophrenia and depression.

CONCLUSIONS: Vitamin D plays a fundamental role in calcium and phosphate homeostasis. A deficiency of vitamin D has been attributed to several diseases. Since its production in the skin depends on exposure to UVB-radiation via the sunlight, the level of vitamin D is of crucial importance for the health of inhabitants who live in the Nordic latitudes where there is diminished exposure to sunlight during the winter season. Therefore, fortification or supplementation of vitamin D is necessary for most of the people living in the northern latitudes during the winter season to maintain adequate levels of circulating 25(OH)D3 to maintain optimal body function and prevent diseases.

The vitamin D pathway: a new target for control of the skin's immune response?

Exp Dermatol. 2008 Aug;17(8):633-9. Epub 2008 Jun 28. Schauber J, Gallo RL.
Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. juergen.schauber@med.uni-muenchen.de

The surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production of antimicrobial peptides (AMPs) is a primary system for protection against infection. Many AMPs can be found on the skin, and these include molecules that were discovered for their antimicrobial properties, and other peptides and proteins first known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered on the skin. They are now known to have two distinct functions; they have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases including atopic dermatitis where cathelicidin induction is suppressed, rosacea, where cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response, and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade. Recent work has unexpectedly identified vitamin D3 as a major factor involved in the regulation of cathelicidin expression. Therapies targeting the vitamin D3 pathway and thereby cathelicidin may provide new treatment modalities in the management of infectious and inflammatory skin diseases.

Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.

J Clin Invest. 2007 Mar;117(3):803-11. Epub 2007 Feb 8. Links Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD, Modlin RL, Gallo RL. Division of Dermatology, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California, USA.

An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.

Sun exposure and vitamin D sufficiency.

Gilchrest BA. Am J Clin Nutr. 2008 Aug;88(2):570S-577S.
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA. bgilchre@bu.edu

Ultraviolet radiation is a carcinogen that also compromises skin appearance and function. Because the ultraviolet action spectra for DNA damage, skin cancer, and vitamin D(3) photosynthesis are identical and vitamin D is readily available from oral supplements, why has sun protection become controversial?

First, the media and, apparently, some researchers are hungry for a new message.

Second, the controversy is fueled by a powerful special interest group: the tanning industry. This industry does not target the frail elderly or inner-city ethnic minorities, groups for whom evidence of vitamin D(3) insufficiency is strongest, but rather fair-skinned teenagers and young adults, who are at highest risk of ultraviolet photodamage.

Third, evolution does not keep pace with civilization. When nature gave humans the appealing capacity for cutaneous vitamin D(3) photosynthesis, life expectancy was <40 y; long-term photodamage was not a concern; and vitamin D(3) deficiency, with its resulting skeletal abnormalities (rickets), was likely to be fatal in early life. In the 21st century, life expectancy approaches 80 y in developed countries, vitamin D(3) is available at the corner store, and the lifetime risk of skin cancer is 1 in 3 among white Americans. Medical and regulatory groups should avoid poorly reasoned, sensationalistic recommendations regarding unprotected ultraviolet exposure. Instead, they should rigorously explore possible cause-and-effect relations between vitamin D(3) status and specific diseases while advocating the safest possible means of ensuring vitamin D(3) sufficiency.

Fourth and most important on vitamin D3

Due to regulations (and even more to be expected from C O D E X), the max daily doses is 5µg. This is at least 10 times less than the absolute minimum, 20 times less than optimum levels. Im practice this means people have to take a handful of pills, (10 to 20) to meet the optimum value. Besides the extreme high cost of all these pills, since you swallow lots of tabs and filler materials, it is far from practical as well. Better take supplements where D3 is implemented within many other ingredients. The synergy will make it work even better! Try PhytoMatrix (25µg/day) or MSMPro (25µg/day).

Vitamin D analogs: mechanism of action and therapeutic applications.

Curr Med Chem. 2001 Nov;8(13):1661-79.

Nagpal S, Lu J, Boehm MF.
Gene Regulation, Bone and Inflammation Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis IN-46285, USA. nagpal_sunil@lilly.com

The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.