Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 197, Issue 1-2, Pages 1-13Publisher
ELSEVIER SCI IRELAND LTD
DOI: 10.1016/S0303-7207(02)00273-3
Keywords
vitamin D; 1 alpha,25(OH)(2)D-3; 24,25(OH)D-3; bone; fracture healing; rapid responses
Categories
Funding
- NIDDK NIH HHS [DK-16595, DK09012-35] Funding Source: Medline
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All biologic responses to vitamin D are now known to arise as a consequence of the metabolism of this seco-steroid into its two principal biologically active metabolites 1alpha,25(OH)(2)-vitamin D-3 (1alpha,25(OH)(2)D-3) and 24R,25(OH)(2)-vitamin D-3 (24R,25(OH)(2)D-3). 1alpha,25(OH)(2)D-3 is the dominant metabolite and produces a wide array of biological responses via interacting both with the classical vitamin D nuclear receptor (VDRnuc) that regulates gene transcription in over 30 target organs and with a putative cell membrane receptor (VDRmem1,25) that mediates rapid (within seconds to minutes) biological responses. Ligand occupancy of VDRmem1,25 is linked to signal transduction systems that can mediate the opening of Ca2+ and chloride voltage gated channels as well as activation of MAP-kinase. MAP-kinase activation in some cells containing VDRmem1,25+VDRnuc then results in cross-talk from VDRmem1,25 to VDRnuc which modulates transactivation of 1alpha,25(OH)(2)D-3 responsive gene promoters. The 24R,25(OH)(2)D-3 metabolite has been shown to be an essential hormone for the process of bone fracture healing. The activity of the enzyme responsible for the production of 24R,25(OH)(2)D-3, the renal 25(OH)D-24-hydroxylase, becomes elevated within 4-11 days after imposition of a tibial fracture, thereby increasing the blood concentrations of 24R,25(OH)(2)D-3 by threefold. The 24R,25(OH)(2)D-3 likely initiates its biological responses via binding to the ligand binding domain of a second cell membrane receptor, the VDRmem24,25, which is stereospecific for 24R,25(OH)(2)D-3 in comparison with 24S,25(OH)(2)D-3 and 1alpha,25(OH)(2)D-3. This report summarizes the status of several current research frontiers in this arena of the vitamin D endocrine system. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
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