Vitamin D: Molecular mechanism of action

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-D_9k 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-D_9k 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.