J Neurogenet. 2005 Jan-Mar;19(1):25-38.
Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population.
Tajouri L, Ovcaric M, Curtain R, Johnson MP, Griffiths LR, Csurhes P, Pender MP, Lea RA.
Genomics Research Centre, School of Health Science, Griffith University Gold Coast, Southport, Queensland, Australia.
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) resulting in accumulating neurological disability. The disorder is more prevalent at higher latitudes. To investigate VDR gene variation using three intragenic restriction fragment length polymorphisms (Apa I, Taq I and Fok I) in an Australian MS case-control population. One hundred and four Australian MS patients were studied with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 104 age-, sex-, and ethnicity-matched controls were investigated as a comparative group. Our results show a significant difference of genotype distribution frequency between the case and control groups for the functional exon 9 VDR marker Taq I (p(Gen) = 0.016) and interestingly, a stronger difference for the allelic frequency (p(All) = 0.0072). The Apa I alleles were also found to be associated with MS (p(All) = 0.04) but genotype frequencies were not significantly different from controls (p(Gen) = 0.1). The Taq and Apa variants are in very strong and significant linkage disequilibrium (D' = 0.96, P < 0.0001). The genotypic associations are strongest for the progressive forms of MS (SP-MS and PP-MS). Our results support a role for the VDR gene increasing the risk of developing multiple sclerosis, particularly the progressive clinical subtypes of MS.
Postepy Hig Med Dosw (Online). 2005 Apr 6;59:129-39.
[Biological activity of calcitriol and its new analogues -- potential therapeutic applications]
[Article in Polish]
Pelczynska K, Jaroszewicz I, Switalska M, Opolski A.
Laboratorium Doswiadczalnej Terapii Przeciwnowotworowej, Zaklad Onkologii Doswiadczalnej Instytutu Immunologii i Terapii Doswiadczalnej PAN, Wroclaw.
Calcitriol is effective not only in the regulation of calcium-phosphate homeostasis, but also in promoting the differentiation and inhibition of proliferation of various cells. Calcitriol seems to be a potent drug with various therapeutic applications, such as regulation of calcium-phosphate homeostasis and treatment of psoriasis, autoimmune diseases, and cancer. Since clinical use of calcitriol is largely limited, due to its undesirable side effect of hypercalcemia, numerous calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. This paper summarizes the current state of knowledge concerning the cellular mechanisms of calcitriol's biological activity and their clinical implications. Such medical application includes treatment (as a single-drug or in combination) of osteoporosis, renal osteodystrophy, psoriasis (calcipotriol or tacalcitol ointment), autoimmunological diseases (including multiple sclerosis), and some cancers. The efforts to obtain new vitamin D3 analogues are also briefly reviewed. The structures and roles of vitamin D receptors in the biological effects of calcitriol and its analogues are discussed.
Endocr Rev. 2005 Aug;26(5):662-87. Epub 2005 Mar 29.
Noncalcemic actions of vitamin D receptor ligands.
Nagpal S, Na S, Rathnachalam R.
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. firstname.lastname@example.org
1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
Mutat Res. 2005 Apr 1;571(1-2):207-19. Epub 2005 Jan 28.
Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers.
Moon SJ, Fryer AA, Strange RC.
Human Genomics Research Group, Institute of Science and Technology in Medicine and Department of Urology, Keele University School of Medicine, University Hospital of North Staffordshire, UK.
Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D3 deficiency. Because 1,25-dihydroxyvitamin D3, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D3 synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.
Curr Drug Targets Inflamm Allergy. 2004 Dec;3(4):377-93.
Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs.
May E, Asadullah K, Zugel U.
Corporate Research Business Area Dermatology, Schering AG, Mullerstrasse 178, D-13342 Berlin, Germany.
Beyond its effects on bone metabolism, calcium and phosphorus homeostasis, 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3), calcitriol) exerts profound effects on the immune system. We here provide an overview over the metabolism, molecular and cellular action of 1,25(OH)(2)D(3) with particular regard to its immunomodulatory function. Effects of 1,25(OH)(2)D(3) on the immune system are manyfold and include suppression of T cell activation, shaping of cytokine secretion patterns, induction of regulatory T cells, modulation of proliferation, and interference with apoptosis. 1,25(OH)(2)D(3) further influences maturation, differentiation, and migration of antigen presenting cells. Altogether, its immunomodulatory potency is comparable to other established immunosuppressants without sharing their typical adverse effects. This profile makes 1,25(OH)(2)D(3) a potential drug for the treatment of immune-mediated diseases. Yet, the
major obstacle for its clinical use, its potent calcemic activity, is not overcome to date. The identification or generation of novel vitamin D derivatives with dissociated calcemic and immunomodulatory properties is therefore a major task. Its success might eventually lead to promising drugs for future therapeutic exploitation of a wide array of immune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and others.
Exp Biol Med (Maywood). 2004 Dec;229(11):1136-42.
Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence.
Cantorna MT, Mahon BD.
Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802, USA. email@example.com
Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The optimal level of vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones. Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. Mechanistically, the data point to a role for vitamin D in the development of self-tolerance. The vitamin D hormone (1,25-dihydroxy vitamin D(3)) regulates T helper cell (Th1) and dendritic cell function while inducing regulatory T-cell function. The net result is a decrease in the Th1-driven autoimmune response and decreased severity of symptoms. This review discusses the accumulating evidence pointing to a link between vitamin D and autoimmunity. Increased vitamin D intakes might decrease the incidence and severity of autoimmune diseases and the rate of bone fracture.