The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed

The actions of 1,25(OH)₂D₃-VDR that have emerged from recent studies include, but clearly transcend, the bone and calcium/phosphate homeostasis effects originally attributed to vitamin D. This new understanding now encompasses many of the tissues formerly reported to contain vitamin D receptors, but for which no function of the vitamin-derived hormone could be ascribed. The insights gained from VDR knockout and allelic variation research confirm and extend these concepts, raising the prospect that, for the purpose of preventive measures, assessment of VDR polymorphisms may ultimately become part of a strategy to better identify and treat persons at risk for common disorders such as osteoporosis, breast cancer, or prostate cancer. We have learned much about VDR structure/function from natural mutations in 1,25-(OH)₂D₃-resistant patients and from site-directed mutagenesis experiments, as well as gained insight from the elucidation of analogous crystal structures for RAR, RXR, and TR. The next few years will no doubt witness a growing structural understanding of VDR, presumably culminating in the crystallographic resolution of physical details of liganded versus unliganded forms of VDR, perhaps in the absence and presence of various protein partners and/or VDRE binding sites. Such structural information should allow for the design of the next generation of synthetic analogs possessing the potential capability of selectivity controlling individual 1,25(OH)₂D₃ responses within the organism. Fundamental investigations also have led to an enhanced appreciation of the sequence of events in nuclear VDR signal transduction, offering promise that we may be able to understand how diverse 1,25(OH)₂D₃ agonists could differentially manipulate these steps in a promoter and/or tissue-specific fashion. Such analogs would therefore be endowed with therapeutic potential not only for classic VDR actions in calcium/phosphate homeostasis and bone mineralization, but also for hyperproliferative skin disorders and various types of cancer. A novel type of analog that will be useful in studies of VDR action is an authentic receptor antagonist, and preliminary reports((200,201)) indicate that this reagent may be available soon. Another new frontier of VDR function at the molecular level is clearly that of characterizing VDR-interacting proteins, and identifying how they mediate 1,25(OH)₂D₃ signaling within the context of specific gene promoters. These biochemical and genetic investigations may reveal mechanisms for potential interactions of 1,25(OH)₂D₃ with signaling pathways for other hormones, growth factors, and cytokines that physiologically modulate the wide array of vitamin D bioeffects.