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It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with Aβ plaques, gliosis and autophagosomes, implicating a non‐genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that Aβ upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding‐partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non‐genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD. In Alzheimer’s brain, Aβ induces a non‐genomic action of vitamin D receptor (VDR) via switching VDR heterodimer partner from retinoid X receptor (RXR) to p53, in impairing autophagosome processing. Pharmacological inhibition of p53 switches VDR back to interaction with RXR and diminishes Aβ plaque load and cognitive deficits.

Background/Aim: An alarming increase in vitamin D deficiency even in sunny regions highlights the need for a better understanding of the genetic background of the vitamin D endocrine system and the molecular mechanisms of gene polymorphisms of the vitamin D receptor (VDR). In this study, the serum levels of 25(OH)D 3 were correlated with common VDR polymorphisms (ApaI, BsmI, FokI, and TaqI) in 98 subjects of a Greek homogeneous rural population. Methods: 25(OH)D 3 concentration was measured by ultra-HPLC, and the VDR gene polymorphisms were identified by quantitative real-time PCR followed by amplicon high-resolution melting analysis. Results: Subjects carrying either the B BsmI (OR: 0.52, 95% CI: 0.27–0.99) or t TaqI (OR: 2.06, 95%: 1.06–3.99) allele presented twice the risk for developing vitamin D deficiency compared to the reference allele. Moreover, subjects carrying 1, 2, or all 3 of these genotypes (BB/Bb, Tt/tt, and FF) demonstrated 2-fold (OR: 2.04, 95% CI: 0.42–9.92), 3.6-fold (OR: 3.62, 95% CI: 1.07–12.2), and 7-fold (OR: 6.92, 95% CI: 1.68–28.5) increased risk for low 25(OH)D 3 levels, respectively. Conclusions: Our findings reveal a cumulative effect of specific VDR gene polymorphisms that may regulate vitamin D concentrations explaining, in part, the paradox of vitamin D deficiency in sunny regions, with important implications for precision medicine.

Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH) 2 D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH) 2 D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH) 2 D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.

The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D 3 (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP 9k , and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14 , S100A8 , SOSTDC1 , and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.

ObjectiveColorectal cancer (CRC) is a major health concern. Vitamin D deficiency is associated with high CRC incidence and mortality, suggesting a protective effect of vitamin D against this disease. Given the strong influence of tumour stroma on cancer progression, we investigated the potential effects of the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on CRC stroma.DesignExpression of vitamin D receptor (VDR) and two 1,25(OH)2D3 target genes was analysed in 658 patients with CRC with prolonged clinical follow-up. 1,25(OH)2D3 effects on primary cultures of patient-derived colon normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were studied using collagen gel contraction and migration assays and global gene expression analyses. Publicly available data sets (n=877) were used to correlate the 1,25(OH)2D3-associated gene signature in CAFs with CRC outcome.ResultsHigh VDR expression in tumour stromal fibroblasts was associated with better overall survival (OS) and progression-free survival in CRC, independently of its expression in carcinoma cells. 1,25(OH)2D3 inhibited the protumoural activation of NFs and CAFs and imposed in CAFs a 1,25(OH)2D3-associated gene signature that correlated with longer OS and disease-free survival in CRC. Furthermore, expression of two genes from the signature, CD82 and S100A4, correlated with stromal VDR expression and clinical outcome in our cohort of patients with CRC.Conclusions1,25(OH)2D3 has protective effects against CRC through the regulation of stromal fibroblasts. Accordingly, expression of VDR and 1,25(OH)2D3-associated gene signature in stromal fibroblasts predicts a favourable clinical outcome in CRC. Therefore, treatment of patients with CRC with VDR agonists could be explored even in the absence of VDR expression in carcinoma cells.

Vitamin D deficiency has been epidemiologically linked to Alzheimer's disease (AD) and other dementias, but no interventional studies have proved causality. Our previous work revealed that the genomic vitamin D receptor (VDR) is already converted into a non‐genomic signaling pathway by forming a complex with p53 in the AD brain. Here, we extend our previous work to assess whether it is beneficial to supplement AD mice and humans with vitamin D. Intriguingly, we first observed that APP/PS1 mice fed a vitamin D‐sufficient diet showed significantly lower levels of serum vitamin D, suggesting its deficiency may be a consequence not a cause of AD. Moreover, supplementation of vitamin D led to increased Aβ deposition and exacerbated AD. Mechanistically, vitamin D supplementation did not rescue the genomic VDR/RXR complex but instead enhanced the non‐genomic VDR/p53 complex in AD brains. Consistently, our population‐based longitudinal study also showed that dementia‐free older adults (n = 14,648) taking vitamin D3 supplements for over 146 days/year were 1.8 times more likely to develop dementia than those not taking the supplements. Among those with pre‐existing dementia (n = 980), those taking vitamin D3 supplements for over 146 days/year had 2.17 times the risk of mortality than those not taking the supplements. Collectively, these animal model and human cohort studies caution against prolonged use of vitamin D by AD patients. We studied whether it is beneficial to supplement vitamin D to APP/PS1 mice and humans. The animal studies show vitamin D deficiency is an early disease outcome and supplementation of vitamin D worsens AD brain pathology via enhancing VDR/p53 complex to impair autophagosome. Nationwide longitudinal cohort studies also suggest long‐term vitamin D supplementation is associated with higher risk of dementia in dementia‐free older adults and higher mortality in dementia individuals. Our results caution against prolonged use of vitamin D by AD patients and older adults.

PurposeThis review provides a current perspective on the mechanism of vitamin D on skeletal muscle function with the emphasis on oxidative stress, muscle anabolic state and muscle energy metabolism. It focuses on several aspects related to cellular and molecular physiology such as VDR as the trigger point of vitamin D action, oxidative stress as a consequence of vitamin D deficiency.MethodThe interaction between vitamin D deficiency and mitochondrial function as well as skeletal muscle atrophy signalling pathways have been studied and clarified in the last years. To the best of our knowledge, we summarize key knowledge and knowledge gaps regarding the mechanism(s) of action of vitamin D in skeletal muscle.ResultVitamin D deficiency is associated with oxidative stress in skeletal muscle that influences the mitochondrial function and affects the development of skeletal muscle atrophy. Namely, vitamin D deficiency decreases oxygen consumption rate and induces disruption of mitochondrial function. These deleterious consequences on muscle may be associated through the vitamin D receptor (VDR) action. Moreover, vitamin D deficiency may contribute to the development of muscle atrophy. The possible signalling pathway triggering the expression of Atrogin-1 involves Src-ERK1/2-Akt- FOXO causing protein degradation.ConclusionBased on the current knowledge we propose that vitamin D deficiency results from the loss of VDR function and it could be partly responsible for the development of neurodegenerative diseases in human beings.

ObjectiveWe assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival.DesignWe sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response.ResultsSerial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1–2). CRP peaked 3–5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I–III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77).ConclusionsCRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.

It is urgent to seek new potential targets for the prevention or relief of gastrointestinal syndrome in clinical radiation therapy for cancers. Vitamin D, mediated through the vitamin D receptor (VDR), has been identified as a protective nutrient against ionizing radiation (IR)-induced damage. This study investigated whether VDR could inhibit IR-induced intestinal injury and explored underlying mechanism. We first found that vitamin D induced VDR expression and inhibited IR-induced DNA damage and apoptosis in vitro. VDR was highly expressed in intestinal crypts and was critical for crypt stem/progenitor cell proliferation under physiological conditions. Next, VDR-deficient mice exposed to IR significantly increased DNA damage and crypt stem/progenitor cell apoptosis, leading to impaired intestinal regeneration as well as shorter survival time. Furthermore, VDR deficiency activated the Pmaip1-mediated apoptotic pathway of intestinal crypt stem/progenitor cells in IR-treated mice, whereas inhibition of Pmaip1 expression by siRNA transfection protected against IR-induced cell apoptosis. Therefore, VDR protects against IR-induced intestinal injury through inhibition of crypt stem/progenitor cell apoptosis via the Pmaip1-mediated pathway. Our results reveal the importance of VDR level in clinical radiation therapy, and targeting VDR may be a useful strategy for treatment of gastrointestinal syndrome.