Molecular and Cellular Endocrinology 453 (2017) 1e2

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Molecular and Cellular Endocrinology

Editorial

Endocrine functions of vitamin D

The name “vitamin D” for the fat-soluble secosteroid cholecal- on the mechanistic actions of VDR focuses on the structural aspects
ciferol implies that humans need to take up this molecule via their of vitamin D endocrinology (Rochel and Molnar, 2017). The ana-
diet since their own catabolism may not be able to produce it. In lyses of crystal structures of VDR, the vitamin D transport protein
contrast, at UV-B (290e315 nm) exposure human skin is able to DBP and the vitamin D metabolizing enzymes CYP2R1 and
synthesize vitamin D on the basis of the cholesterol precursor 7- CYP24A1, provide atomic scale insight on the mechanisms of
dehydrocholesterol. Thus, insufficient exposure to sunlight in pop- vitamin D signaling on the level of protein structure. This structural
ulations living at Northern latitudes and/or primarily indoors made perspective nicely complements the bioinformatic and epigenomic
the vitamin D status of many individuals dependent on diet, such as views on the endocrinology of vitamin D and provides mechanistic
fatty fish, and cod oil supplementation. This led to the misleading explanations on a number of vitamin D-associated diseases, such as
classification of the molecule as a vitamin. Vitamin D itself is biolog- hereditary vitamin D-resistant rickets.
ically inert, but its metabolite 1,25-dihydroxyvitamin D The evolutionary oldest and probably still prime physiological
(1,25(OH)2D, also referred to as calcitriol) is a high-affinity ligand action of vitamin D endocrinology, the control of calcium homeo-
of the transcription factor vitamin D receptor (VDR). The nuclear re- stasis, is discussed next (Fleet, 2017). Vitamin D regulates serum
ceptor VDR is expressed in the majority of human tissues and cell calcium within a very narrow range by coordinating the action of
types, in particular in pituitary gland, parathyroid gland, small in- small intestine, kidney, bone and parathyroid gland, tissues in
testine, colon, kidney, skin and many cell types of the immune sys- which largest VDR expression is found. In turn, aging, growth, preg-
tem, and controls the transcription of in total more than 1000 nancy and menopause as well as dietary calcium intake modulate
genes. Thus, vitamin D is a pre-hormone that via its hormonal the production of 1,25(OH)2D and by this the activity of VDR in mul-
metabolite 1,25(OH)2D has endocrine regulatory functions on a tiple tissues. The main purpose of calcium homeostasis is to assure
larger number of physiological processes, many of which are dis- sufficient calcium delivery for bone mineralization, as discussed by
cussed in the 14 review articles of this Special Issue. the following review (van Driel and van Leeuven, 2017). Since bone
The issue starts with a reflection how bioinformatic analysis of is a dynamic tissue in equilibrium between resorption of its extra-
recently obtained large-scale data, such as chromatin immunopre- cellular matrix by macrophage-type osteoclast and its formation by
cipitation sequencing (ChIP-seq) of VDR in various cellular systems, osteoblasts, bone maintenance is critically dependent on vitamin D
genome-wide association studies for multiple common diseases or and other hormones, such as parathyroid hormone and glucocorti-
whole genome sequencing of more than 10,000 cancer patients, coids. Osteoblasts are the key cell type in human bone mineraliza-
can provide an unbiased view on the physiological impact of tion and they are stimulated by 1,25(OH)2D. VDR expression levels
vitamin D signaling (Campbell, 2017). The article concludes that change during the osteoblast differentiation process, which is of
vitamin D and its receptor are implicated in bone biology and the critical impact for the network of VDR target genes in these cells.
function of the immune system, but there is no indication that The following two reviews discuss another important physio-
VDR is directly involved in tumorigenesis. Large-scale data are logical function of vitamin D, the modulation of the immune sys-
also discussed in the following review (Carlberg, 2017) but with tem, i.e. its gene regulatory effects on cells of the innate
focus on the epigenome, i.e. on the packaging of the genome within (monocytes, macrophages and dendritic cells) and adaptive im-
chromatin, and its impact on vitamin D-regulated gene expression. mune system (B and T lymphocytes). A number of key mediators
The integration of a larger set of genome- and transcriptome-wide of immune signaling, such as cytokines and membrane proteins,
data that were all obtained under identical conditions in human are primary and secondary vitamin D target genes, but interestingly
monocytes (THP-1) proposes a model of epigenomic vitamin D also many members of metabolic pathways, such as enzymes and
signaling that may serve also for other tissues and cell types: i) in transporters, are VDR targets in immune cells (Vanherwegen
the absence of 1,25(OH)2D VDR binds to a limited number of chro- et al., 2017). The metabolic states of immune subsets are very dy-
matin loci, ii) ligand stimulation increases VDR binding both in namic and vitamin D appears to be a key regulator of this
number of loci as well as in strength, iii) pioneer transcription fac- immune-metabolism. The insight that cellular metabolism shapes
tors support the access of VDR to genomic DNA, iv) vitamin D stim- the phenotype of immune cells allows a more detailed understand-
ulation and VDR binding increase chromatin accessibility at several ing of the role of vitamin D in inflammation and autoimmune dis-
thousand sites, v) as a consequence of which the binding of the eases and their possible therapy. Inflammatory bowel disease (IBD),
chromatin organizing transcription factor CTCF and its formation in particular its sub-form Crohn's disease, is one of these chronic
of topologically associating domains is modulated. Taken together, diseases, the conditions of which were shown to be improved by
vitamin D significantly affects the epigenome of its target tissues vitamin D supplementation (Dimitrov and White, 2017). Vitamin
before and while the transcriptome is stimulated. A third review D target genes encoding for pattern recognition receptors, anti-

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2 Editorial / Molecular and Cellular Endocrinology 453 (2017) 1e2

microbial peptides and cytokines in innate immune cells located impairment and neurodegeneration. The latter is in part due to
within the intestine are involved in sensing microbiota, in prevent- the fact that during aging vitamin D metabolism and activity
ing their overgrowth and in enhancing the intestinal barrier func- changes (de Jongh et al., 2017). This includes reduced intestinal cal-
tion. In parallel, vitamin D stimulates the differentiation of T cells cium uptake and lower expression of VDR and vitamin D metabo-
into a tolerogenic phenotype. This demonstrates that immune- lizing enzymes. Thus, appropriate vitamin D supplementation of
modulatory effects of vitamin D on the innate and adaptive im- elderly has positive effects on fracture risk, number of falls and
mune system are critical for barrier integrity in the gut and its mi- physical function.
crobial load and composition. In summary, the 14 review articles of this Special Issue present
Three review articles connect the endocrinology of vitamin D the wide physiological impact of vitamin D endocrinology ranging
with cellular growth. The double function of vitamin D in small in- from the tight control of calcium homeostasis and bone formation
testine and colon, i.e. absorption of calcium and barrier function, to the modulation of innate and adaptive immunity. Vitamin D
emphasizes its critical role in gut physiology and homeostasis endocrinology affects chronic inflammatory diseases, cancer,
(Barbachano et al., 2017). In turn, vitamin D deficiency is associated fertility and neurodegeneration and needs to be appropriately trig-
with an increased risk of colorectal cancer. This suggests that gered by vitamin D supplementation during pregnancy as well as in
vitamin D and its synthetic analogs have the potential to prevent aging.
and/or treat this common type of cancer, a finding that is supported
by bioinformatic analysis of large-scale tumor data (Campbell,
2017). The cell growth regulatory potential of vitamin D was first
References
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seem to be based on non-nuclear localization of VDR. These regula- School of Medicine, Institute of Biomedicine, University of Eastern
tory effects of vitamin D are linked to brain ontogeny as well as to Finland, FIN-70211 Kuopio, Finland
functional neurochemical and behavioral outcomes. Vitamin D E-mail address: carsten.carlberg@uef.fi.
deficiency during brain development can lead to schizophrenia
and autism and in elderly persons it is associated with cognitive Available online 29 June 2017