科研之友
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摘要
Cholecalciferol was described as a "vitamin", which can cure rickets. The consecutive in-depth characterization of this system revealed an unexpected complexity. Upon the identification of the classical vitamin D receptor VDR a huge proportion of the vitamin D effects could be assigned to the field of steroid hormone receptor signaling. The secosteroid hormone 1,25 dihydroxycholecalciferol 1,25-D-3 binds to the transcription factor VDR and modulates gene regulation. The signaling cascade involves the retinoic acid X receptor RXR as a VDR dimerisation partner, thus adding a level of only partially unraveled complexity, where vitamin D and vitamin A dependent signal transduction interact. Vitamin D-3 metabolites exert rapid membrane associated effects, which cause second messenger phenomena within seconds and minutes. It has become clear now that membrane associated VDR is responsible for some of these effects. However, recent work identified the 1,25-D-3-MARRS (membrane associated rapid response to steroids) receptor protein (PDIA3) as a high affinity membrane-associated binding protein, which exerts both own and downstream converging effects. PDIA3 belongs to a family of protein disulfide isomerases and is also capable of translocating to the nucleus. Vitamin D-3 metabolism as a multifaceted system adds one more level of complexity in that besides systemic supply via liver and kidney peripheral tissues may become completely autonomous by locally expressing all relevant enzymes. With a focus on bone 1,25-D-3 systemically has pro-mineralizing effects through stimulation of intestinal calcium and phosphate absorption via both receptor systems. In bone microenvironment 1,25-D-3 has a more balancing profile in that it also strongly inhibits overmineralization via e. g. osteocalcin and osteopontin and VDR/osteoblasts display enhanced osteogenic capacity. Besides bone its pleiotropic effects on cell differentiation and inhibition of proliferation are putatively highly relevant for the regulation of metabolism and the cardiovascular systems as well as carcinogenesis, while prospective studies will have to prove the latter in addition to already strong associative data.
- 出版日期2011
