1. Br J Pharmacol. 2009 Apr 9. [Epub ahead of print] Related Articles, Links
Potential for vitamin D receptor agonists in the treatment of cardiovascular disease
Abbott, Abbott Park, IL, USA
Vitamin D(3) is made in the skin and modified in the liver and kidney to form the active metabolite, 1,25-dihydroxyvitamin D(3) (calcitriol). Calcitriol binds to a nuclear receptor, the vitamin D receptor (VDR), and activates VDR to recruit cofactors to form a transcriptional complex that binds to vitamin D response elements in the promoter region of target genes. During the past three decades the field has focused mainly on the role of VDR in the regulation of parathyroid hormone, intestinal calcium/phosphate absorption and bone metabolism; several VDR agonists (VDRAs) have been developed for the treatment of osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney disease (CKD). Emerging evidence suggests that VDR plays important roles in modulating cardiovascular, immunological, metabolic and other functions. For example, data from epidemiological, preclinical and clinical studies have shown that vitamin D and/or 25(OH)D deficiency is associated with increased risk for cardiovascular disease (CVD). However, VDRA therapy seems more effective than native vitamin D supplementation in modulating CVD risk factors. In CKD, where decreasing VDR activation persists over the course of the disease and a majority of the patients die of CVD, VDRA therapy was found to provide a survival benefit in both pre-dialysis and dialysis CKD patients. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present no VDRA is approved for CVD, and also no serum markers, beside parathyroid hormone in CKD, exist to indicate the efficacy of VDRA in CVD.
2. Mol Aspects Med. 2008 Dec;29(6):407-14. Epub 2008 Aug 8. Related Articles, Links
Vitamin D and skeletal muscle tissue and function
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Bone Metabolism Laboratory, 711 Washington Street, Boston, MA 02111, USA. email@example.com
This review aims to summarize current knowledge on the role of vitamin D in skeletal muscle tissue and function. Vitamin D deficiency can cause a myopathy of varying severity. Clinical studies have indicated that vitamin D status is positively associated with muscle strength and physical performance and inversely associated with risk of falling. Vitamin D supplementation has shown to improve tests of muscle function, reduce falls, and possibly impact on muscle fiber composition and morphology in vitamin D deficient older adults. Molecular mechanisms of vitamin D action on muscle tissue include genomic and non-genomic effects via a receptor present in muscle cells. Genomic effects are initiated by binding of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] to its nuclear receptor, which results in changes in gene transcription of mRNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a cell surface receptor. Knockout mouse models of the vitamin D receptor provide insight into understanding the direct effects of vitamin D on muscle tissue. Recently, VDR polymorphisms have been described to affect muscle function. Parathyroid hormone which is strongly linked with vitamin D status also may play a role in muscle function; however, distinguishing its role from that of vitamin D has yet to be fully clarified. Despite the enormous advances in recent decades, further research is needed to fully characterize the exact underlying mechanisms of vitamin D action on muscle tissue and to understand how these cellular changes translate into clinical improvements in physical performance.
3. Bioessays. 2008 Feb;30(2):173-82. Related Articles, Links
Comment in: Bioessays. 2008 May;30(5):506-7; author reply 510-1.
Bioessays. 2008 May;30(5):508-9; author reply 510-1.
Vitamin D discovery outpaces FDA decision making
School of Biological Sciences and Biotechnology, Murdoch University, Western Australia. firstname.lastname@example.org
The US FDA currently encourages the addition of vitamin D to milk and cereals, with the aim of reducing rickets in children and osteoporosis in adults. However, vitamin D not only regulates the expression of genes associated with calcium homeostasis, but also genes associated with cancers, autoimmune disease, and infection. It does this by controlling the activation of the vitamin D receptor (VDR), a type 1 nuclear receptor and DNA transcription factor. Molecular biology is rapidly coming to an understanding of the multiplicity of roles played by the VDR, but clinical medicine is having difficulty keeping up with the pace of change. For example, the FDA recently proposed a rule change that will encourage high levels of vitamin D to be added to even more foods, so that the manufacturers can claim those foods "reduce the risk of osteoporosis". The FDA docket does not review one single paper detailing the transcriptional activity of vitamin D, even though, on average, one new paper a day is being published on that topic. Nor do they review whether widespread supplementation with vitamin D, an immunomodulatory secosteroid, might predispose the population to immune dysfunction. This BioEssay explores how lifelong supplementation of the food chain with vitamin D might well be contributing to the current epidemics of obesity and chronic disease. (c) 2008 Wiley Periodicals, Inc.
4. Acta Pharmacol Sin. 2007 Sep;28(9):1373-82. Related Articles, Links
Vitamin D and prevention of breast cancer
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA. email@example.com
Epidemiologic data have demonstrated that breast cancer incidence is inversely correlated with indices of vitamin D status, including ultraviolet exposure, which enhances epidermal vitamin D synthesis. The vitamin D receptor (VDR) is expressed in mammary epithelial cells, suggesting that vitamin D may directly influence sensitivity of the gland to transformation. Consistent with this concept, in vitro studies have demonstrated that the VDR ligand, 1,25-dihydroxyvitamin D (1, 25D), exerts negative growth regulatory effects on mammary epithelial cells that contribute to maintenance of the differentiated phenotype. Furthermore, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis in the mammary gland, which ultimately enhances its susceptibility to carcinogenesis. In addition, dietary supplementation with vitamin D, or chronic treatment with synthetic VDR agonists, reduces the incidence of carcinogen-induced mammary tumors in rodents. Collectively, these observations have reinforced the need to further define the human requirement for vitamin D and the molecular actions of the VDR in relation to prevention of breast cancer.
5. Pharmacogenet Genomics. 2005 Feb;15(2):127-35. Related Articles, Links
Vitamin D receptor genotypes influence the success of calcitriol therapy for recurrent vertebral fracture in osteoporosis
Morrison NA, George PM, Vaughan T, Tilyard MW, Frampton CM, Gilchrist NL
School of Health Sciences, Gold Coast Campus, Griffith University, Queensland, Australia. firstname.lastname@example.org
Osteoporosis is a complex multi-factorial disease where environment, diet and genetics play a role in determining susceptibility. Patients with existing vertebral fracture have a heightened risk of further recurrent vertebral fracture. The efficacy of new osteoporosis therapies is often compared to calcium supplementation. 1,25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) and is effective at reducing recurrent vertebral fracture risk. Because the VDR controls calcium metabolism, we hypothesized that genetic variation at the VDR locus may influence response to both calcium and calcitriol therapy. Postmenopausal women with osteoporosis from a 3-year study comparing calcitriol versus calcium for prevention of vertebral fractures were genotyped for VDR alleles detected by FokI, BsmI, ApaI and TaqI. Data were analysed by hierarchical log-linear analysis and robust analysis of variance for relationships to fracture outcomes. Significant differences in the vertebral fracture rate in response to calcium therapy were observed between VDR genotypes (P<0.001). Calcium appeared to be equally effective as calcitriol in particular genotypes. The response to calcitriol therapy was most pronounced in patients carrying the TaqI t allele in combination with the FokI f initiation codon variant: f+t+ carriers were 11.3-fold less likely to sustain recurrent vertebral fracture in the last 2 years of the trial while on calcitriol therapy compared to calcium (P=1.4x10(-5)). Response to both calcium and calcitriol therapy is dependent on genetic variation at the VDR locus and two loci in the VDR gene may contribute to this effect.
6. Clin Calcium. 2003 Jul;13(7):905-7. Related Articles, Links
Effect of calcium and vitamin D on skeletal muscle
Article in Japanese
Endo I, Inoue D
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine.
Patients with vitamin D insufficiency often exhibit muscle weakness and/or atrophy which can be cured by vitamin D and Ca supplementation. However, its molecular mechanism is largely unknown. The direct effects of vitamin D on skeletal muscle cells include induction of transcription factors such as c-myc (genomic action) ;and activation of Ca channels, Src tyrosine kinase and MAP kinase (non-genomic action). Recent studies on VDR gene knockout mice revealed that VDR also regulates expression of the MyoD family of transcription factors in skeletal muscle. Thus, vitamin D and Ca appear to regulate proliferation, maturation and function of skeletal muscle through these complex actions.
7. Clin Calcium. 2003 Jul;13(7):869-74. Related Articles, Links
Dietary calcium and VDR gene polymorphism's interaction
Article in Japanese
Hisada K, Nishizawa K, Tokita A
Department of Pediatrics, Juntendo University School of Medicine.
The fundamental role of vitamin D receptor (VDR) gene polymorphisms have been reviewed. The VDR gene polymorphisms are associated with the intestinal calcium absorption , rate of bone gain and loss. The observed variability in younger and elderly people in the response of bone mass to calcium intake and supplementation may be explained partly by the interaction between environmental and genetic factors.
（摘自Vitamin D Today）