Editorial [Hot topic: Newly Recognized Actions of Vitamin D3 (Guest Editor: Ilka Nemere)]

Vitamin D and its metabolites have been the focus of attention recently, and as stated in the title, this issue highlights some of the newly recognized actions of these compounds. In the first paper, Sequeira et al. begin with the metabolism of vitamin D to other metabolites and the classical role of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in the regulation of calcium homeostasis. The authors then relate the evidence that 1,25(OH)2D3 can be made in the skin following UV irradiation, and as widely known, UV irradiation also causes DNA damage and skin cancer. Of utmost importance however, is that 1,25(OH)2D3 is protective against skin cancer, and this appears to occur through a membrane-associated pathway rather than through gene regulation. Boyan and co-workers report on the progress they have made in studying the effects of the metabolite 24,25- dihydroxyvitamin D3 in growth plate chondrocytes. 24,25(OH)2D3, which was once thought to be inactive, rapidly alters phospholipase activities and protein kinase C. The latter is involved in matrix synthesis and chondrocyte activation. 24,25(OH)2D3 also has an anti-apoptotic function that is induced by inorganic phosphate. The receptor for this metabolite could be a new therapeutic target in regulating ossification. Our paper discusses newly recognized receptors for both 1,25(OH)2D3 and 24,25(OH)2D3. The 1,25D3-MARRS (membrane associated, rapid response, steroid binding) receptor has been shown to mediate the pregenomic responses in chick both by RNAi and a neutralizing antibody. The classical VDR was found to not be involved. By comparison, rat intestinal cells use both the 1,25D3-MARRS receptor and the VDR. 24,25(OH)2D3 acts as an endogenous inhibitor of the rapid actions of 1,25(OH)2D3 in chick intestine and kidney. The inhibitory steroid binds to cell surface catalase resulting in decreased enzyme activity. The resulting increase in hydrogen peroxide acts to oxidized the thioredoxin domains in the 1,25D3-MARRS receptor. This in turn decreases binding of 1,25(OH)2D3. In the same studies, no effect was found on binding of 1,25(OH)2D3 to the classical VDR. These studies indicate that the 1,25D3-MARRS receptor is a potential therapeutic target for modulating intestinal calcium and phosphate absorption. In the comprehensive review by Buitrago et al., the authors summarize evidence from their lab and others on the effects of 1,25(OH)2D3 and estradiol on skeletal muscle. Both the classical VDR and ER were found in plasma membrane and mitochondria. Both steroid hormones also use tyrosine receptor kinases for signaling, as well as an array of other signaling pathways. Both hormones stimulate muscle cell proliferation and inhibit apoptosis-a physiological effect that may prove useful in treating muscle weakening from ageing and myopathies.