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Preclinical data strongly suggest that the vitamin D endocrine system (VDES) may have extraskeletal effects. Cells of the immune and cardiovascular systems and lungs can express the vitamin D receptor, and overall these cells respond in a coherent fashion when exposed to 1,25-dihydroxyvitamin D, the main metabolite of the VDES. Supplementation of vitamin D-deficient subjects may decrease the risk of upper respiratory infections. The VDES also has broad anti-inflammatory and anti-thrombotic effects, and other mechanisms argue for a potential beneficial effect of a good vitamin D status on acute respiratory distress syndrome, a major complication of this SARS-2/COVID-19 infection. Activation of the VDES may thus have beneficial effects on the severity of COVID-19. Meta-analysis of observational data show that a better vitamin D status decreased the requirement of intensive care treatment or decreased mortality. A pilot study in Cordoba indicated that admission to intensive care was drastically reduced by adminial Research.Muscle weakness has been recognized as a hallmark feature of vitamin D deficiency for many years. Until recently, the direct biomolecular effects of vitamin D on skeletal muscle have been unclear. Although in the past, some reservations have been raised regarding the expression of the vitamin D receptor in muscle tissue, this special issue review article outlines the clear evidence from preclinical studies for not only the expression of the receptor in muscle but also the roles of vitamin D activity in muscle development, mass, and strength. Additionally, muscle may also serve as a dynamic storage site for vitamin D, and play a central role in the maintenance of circulating 25-hydroxy vitamin D levels during periods of low sun exposure. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Vitamin D is well known for its role as a calcium regulator and in maintenance of phosphate homeostasis in musculoskeletal health, and fibroblast growth factor 23 (FGF23) and its coreceptor α-klotho are known for their roles as regulators of serum phosphate levels. However, apart from these classical actions, recent data point out a relevant role of vitamin D and FGF23/klotho in lung health. The expression of the vitamin D receptor by different cell types in the lung and the fact that those cells respond to vitamin D or can locally produce vitamin D indicate that the lung represents a target for vitamin D actions. Similarly, the presence of the four FGF receptor isoforms in the lung and the ability of FGF23 to stimulate pulmonary cells support the concept that the lung is a target for FGF23 actions, whereas the contribution of klotho is still undetermined. This review will give an overview on how vitamin D or FGF23/klotho may act on the lung and interfere positively or negatively with lung health. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.In this review we summarize the impact of bolus versus daily dosing of vitamin D on 25(OH)D and 1,25(OH)2D levels, as well as on key countervailing factors that block vitamin D functions at the cellular level. Further, we discuss the role of bolus versus daily dosing of vitamin D for several health outcomes, including respiratory infections and coronavirus disease 2019 (COVID-19), rickets, falls and fractures, any cancer, and cancer-related mortality. This discussion appears timely because bolus doses continue to be tested for various disease outcomes despite a growing amount of evidence suggesting lack of efficacy or even detrimental effects of bolus dosing of vitamin D for outcomes where daily dosing at modest levels was effective in the vitamin D deficient. As a result, these discordant results may bias health recommendations for vitamin D if the recommendations are based on meta-analyses combining both daily and bolus dosing trials. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Apart from its phosphaturic action, the bone-derived hormone fibroblast growth factor-23 (FGF23) is also an essential regulator of vitamin D metabolism. The main target organ of FGF23 is the kidney, where FGF23 suppresses transcription of the key enzyme in vitamin D hormone (1,25(OH)2D) activation, 1α-hydroxylase, and activates transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase, in proximal renal tubules. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in bone, forming a feedback loop between kidney and bone. The importance of FGF23 as regulator of vitamin D metabolism is underscored by the fact that in the absence of FGF23 signaling, the tight control of renal 1α-hydroxylase fails, resulting in overproduction of 1,25(OH)2D in mice and men. During recent years, big strides have been made toward a more complete understanding of the mechanisms underlying the FGF23-mediated regulation of vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. Importantly, the intracellular signaling cascades downstream of FGF receptors regulating transcription of 1α-hydroxylase and 24-hydroxylase in proximal renal tubules still remain unresolved. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the regulation of vitamin D metabolism by FGF23, and to discuss the role of these mechanisms in physiology and pathophysiology. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.The vitamin D hormone, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), and related compounds derived from vitamin D3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV-induced DNA damage with 20-hydroxyvitamin D3 or 24-hydroxylumisterol3, as previously shown for 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)2D3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)2D3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1α-hydroxylase and thus unable to make 1,25(OH)2D3 are not more susceptible. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Calcium is required for the functioning of numerous biological processes and is essential for skeletal health. The major source of new calcium is from the diet. The central role of vitamin D in the maintenance of calcium homeostasis is to increase the absorption of ingested calcium from the intestine. The critical importance of vitamin D in this process is noted in the causal link between vitamin D deficiency and rickets, as well as in studies using genetically modified mice including mice deficient in the vitamin D receptor (Vdr null mice) or in the cytochrome P-450 enzyme, 25-hydroxyvitamin D3-1α- hydroxylase (CYP27B1) that converts 25-hydroxyvitamin D3 to the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (Cyp27b1 null mice). When these mice are fed diets with high calcium and lactose, rickets is prevented. The studies using mouse models provide supporting evidence indicating that the major physiological function of 1,25(OH)2D3/VDR is intestinal calcium absorption. This review summarizes what is known about mechanisms involved in vitamin D-regulated intestinal calcium absorption. Recent studies suggest that vitamin D does not affect a single entity, but that a complex network of calcium-regulating components is involved in the process of 1,25(OH)2D3-mediated active intestinal calcium absorption. Selleckchem CDK inhibitor In addition, numerous 1,25(OH)2D3 actions in the intestine have been described independent of calcium absorption. Although the translatability to humans requires further definition, an overview is presented that provides compelling evidence from the laboratory of 1,25(OH)2D3 intestinal effects, which include the regulation of adhesion molecules to enhance barrier function, the regulation of intestinal stem cell function, cellular homeostasis of other divalent cations, the regulation of drug metabolizing enzymes, and anti-inflammatory effects. © 2021 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Nationally representative data on vitamin D intake can inform on the adequacy of dietary supply of vitamin D in a population, but such data is lacking for a majority of countries. Estimates of average per capita supply of vitamin D, as calculated using information from the Food and Agriculture Organisation of the United Nations (FAO) national food balance sheets (FBSs) can be used as proxy measures for vitamin D intake within a population. In the present work, FAO national FBSs (from 2004 to 2017) for 173 to 178 countries around the globe were used to generate such average per capita vitamin D supply estimates. For countries where food fortification with vitamin D was common, the estimates accounted for this. Using the 2004-2013 FBS data, there was a large range in average per capita vitamin D supply ranging from 0.3 (Ethiopia) to 17.8 (Maldives) μg/d. Globally, 40, 60, 70, four, two, and two countries had average per capita vitamin D supply estimates 7.6 μg/d. Median per capita vitamin D supply estimates for constituent countries within Africa, Americas, Asia, Europe, and Oceania were 1.4, 2.7, 2.8, 4.1, and 4.7 μg/d, respectively. These overall supply trends were mirrored in the newer, 2014-2017 FBS data. Fortification of milk and dairy or wheat flour with vitamin D had an important impact on the vitamin D supply estimates (average increments of 1.6 and 3.1 μg/d, respectively). Overall, the work showed how the per capita daily vitamin D supply estimates, as surrogate for vitamin D intake data, can highlight countries where inadequacy of supply may be of concern. It also shows how fortification of food with vitamin D can have an important impact on addressing low vitamin D intake. © 2021 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.