title: Control of Inflammatory Bowel Disease and Colorectal Cancer by Synthetic Vitamin D Receptor Ligands.
abstract: Vitamin D deficiency and insufficiency are associated with an increased risk of cancer, autoimmune disease, inflammation, infection, cardiovascular disease and metabolic disease, as well as bone and mineral disorders. The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, is a receptor for the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and mediates vitamin D regulation of specific target gene expression. The secondary bile acid lithocholic acid, which is produced by intestinal bacteria, is another natural VDR ligand. VDR signaling has been suggested to be involved in reciprocal communication between intestinal cells, including immune and epithelial cells, and intestinal microflora. In addition to epidemiological studies on vitamin D status, genome-wide analyses and cellular and animal experiments have shown that VDR is involved in the prevention of inflammatory bowel disease (IBD) and colorectal cancer (CRC). VDR deletion in mice exaggerates colitis and colon tumorigenesis in experimental models, and treatment of mice with synthetic vitamin D analogues ameliorates pathological changes in these diseases. Several VDR ligands are less active in increasing serum calcium levels, showing higher therapeutic efficiency than the natural hormone 1,25(OH)2D3. VDR plays a role in intestinal homeostasis and in protection against IBD and CRC. The development of VDR ligands with reduced or no calcemic activity will be necessary to expand clinical application of VDRtargeting therapy.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610. Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173- 8610. Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000517:prevention & control*; D008024:Ligands; D018167:Receptors, Calcitriol / Q000378:metabolism*
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol
keywords: Vitamin D receptor; bile acids; colorectal cancer; hypercalcemia; inflammatory bowel disease; selective VDR modulator; vitamin D analogues