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Part III. Regulation of Skeletal Remodeling |
Vitamin DMolecular Mechanism of Action
SYLVIA CHRISTAKOSa,
PUNEET DHAWANa,
BRYAN BENNa,
ANGELA PORTAa,
MATTHIAS HEDIGERb,
GOO T. OHc,
EUI-BAE JEUNGd,
YAN ZHONGa,
DARE AJIBADEa,
KOPAL DHAWANa AND
SNEHA JOSHIa
a Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA b Institute for Biochemistry and Molecular Biology, University of Bern, CH-3012 Berne, Switzerland c Laboratory of Cardiovascular Genomics, Ewha Woman's University, Seoul 120-750, Korea d Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Chungbuk 361-763, Korea
Key Words: calbindin • TRPV6 epithelial calcium channel • vitamin D • 1,25-dihydroxyvitamin D3 • osteopontin • parathyroid hormone • 25-hydroxyvitamin D3 24-hydroxylase
Address for correspondence: Dr. Sylvia Christakos, Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103. Voice: 973-972-4033; fax: 973-972-5594. christak{at}umdnj.edu
Vitamin D maintains calcium homeostasis and is required for bone development and maintenance. Recent evidence has indicated an interrelationship between vitamin D and health beyond bone, including effects on cell proliferation and on the immune system. New developments in our lab related to the function and regulation of target proteins have provided novel insights into the mechanisms of vitamin D action. Studies in our lab have shown that the calcium-binding protein, calbindin, which has been reported to be a facilitator of calcium diffusion, also has an important role in protecting against apoptotic cell death in different tissues including protection against cytokine destruction of osteoblastic and pancreatic β cells. These findings have important implications for the therapeutic intervention of many disorders including diabetes and osteoporosis. Recent studies in our laboratory of intestinal calcium absorption using calbindin-D9k null mutant mice as well as mice lacking the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inducible epithelial calcium channel, TRPV6, provide evidence for the first time of calbindin-D9k and TRPV6 independent regulation of active calcium absorption. Besides calbindin, the other major target of 1,25(OH)2D3 in intestine and kidney is 25(OH)D3 24 hydroxylase (24(OH)ase), which is involved in the catabolism of 1,25(OH)2D3. In our laboratory we have identified various factors that cooperate with the vitamin D receptor in regulating 24(OH)ase expression including C/EBP β, SWI/SNF (complexes that remodel chromatin using the energy of ATP hydrolysis) and the methyltransferases, CARM1 and G9a. Evidence is also presented for C/EBP β as a nuclear coupling factor that coordinates regulation of osteopontin by 1,25(OH)2D3 and PTH. Our findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)2D3 mediates its multiple biological effects.
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