The 1,25-dihydroxyvitamin D3-independent actions of the vitamin D receptor in skin

doi:10.1016/j.jsbmb.2010.03.072

The Journal of Steroid Biochemistry and Molecular Biology

Volume 121, Issues 1–2, July 2010, Pages 317-321

https://doi.org/10.1016/j.jsbmb.2010.03.072 Get rights and content

Abstract

The vitamin D endocrine system plays important but poorly understood roles in the skin and in hair follicle cycling. Rare, human genetic disorders and knockout mouse models highlight essential roles and potentially novel mechanisms of the vitamin D endocrine system in the skin. Vitamin D receptor knockout mice express a hair follicle cycling defect and a hyperproliferative phenotype resulting in disordered skin structure, epidermal thickening, and alopecia. In contrast, ligand knockout mice (i.e., mice with a disrupted CYP27B1 gene that encodes the 25-hydroxyvitamin-D₃ 1α-hydroxylase) have normal hair follicle function and a comparatively modest skin phenotype. These disparate models indicate that VDR may function independently of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) in regulating hair follicle cycling and skin biology. Recent studies highlight this concept and provide key support for this hypothesis. While VDR knockout mice are highly susceptible to chemically induced skin tumorigenesis, CYP27B1 knockouts are resistant. These studies reveal a second global physiological process in the skin that may be regulated by VDR in a 1,25(OH)₂D₃-independent fashion, namely, genoprotection against carcinogenic mutagens. Key cellular and molecular data supporting this mechanism were published recently showing a keratinocyte-selective transactivation activity mediated by VDR that is independent of the 1,25(OH)₂D₃ ligand. Thus, evidence is building to support a potentially novel, 1,25(OH)₂D₃-independent mechanism through which VDR functions in keratinocytes and perhaps within stem cell populations in the follicle to regulate genoprotection and other key developmental processes in the skin.

Section snippets

The vitamin D endocrine system

The bioactive metabolite of vitamin D is 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). It is the hormone of the vitamin D endocrine system and the high affinity ligand of the vitamin D receptor (VDR). The vitamin D endocrine system is part of a multi-hormonal system that directs mineral homeostasis, protects skeletal integrity, and modulates cell growth and differentiation in bone as well as in a diversity of other cell types [1]. Indeed, rickets and osteomalacia are hallmarks of the vitamin D

Mouse knockout models point to novel mechanisms of VDR in the skin

The development of mouse models in which the two key components of the vitamin D endocrine system (namely, the receptor and the ligand) have been genetically disrupted has led to a vastly improved insight into the significance of vitamin D in mammalian biology. There are four published mouse strains with targeted deletions in the VDR gene [8], [9], [10], [11] and two strains targeting CYP27B1 [12], [13]. The VDR knockout (VDRKO) mice present with a phenotype that is remarkably similar to HVDRR.

VDR and skin, potential interplays with Hairless

A candidate protein that may be central to the mechanism of gene repression by apo-VDR is Hairless (Hr), a transcriptional repressor that interacts with nuclear receptors including the VDR [24], [25]. Previous studies indicate that hair loss in VDRKO mice is associated with generalized atrichia, development of deep dermal cysts and utriculi [17], [25], [26], [27]. Notably, mutations in the Hairless gene also leads to alopecia in humans and mice [28], [29], [30]. Zinser et al. highlighted the

VDR protects against chemically induced skin tumorigenesis

VDRKO mice are also highly sensitive to DMBA-induced skin tumorigenesis [27], [34]. VDRKO mice develop skin tumors with 100% penetrance and a mean latency of approximately 10 weeks following oral DMBA administration. This rapid onset in the VDRKO animals is contrasted with the wild-type animals that do not develop skin tumors for periods up to 30 weeks post-DMBA treatment. Like the wild-type animals, the 1αOHaseKO mice are also completely resistant to skin tumor formation induced by oral DMBA

VDRKO mice are highly susceptible to UV-induced skin tumorigenesis

While chemical carcinogenesis is a useful paradigm to examine in vivo skin carcinogenesis in laboratory animals, the major environmental risk factor in human skin carcinogenesis is exposure to ultraviolet light [35]. In particular, UVB light (i.e., wavelengths between 290 and 320 nm) induces DNA damage through the formation of cyclobutane pyrimidine dimers [36] and [6–4] photoproducts [37]. Failure to adequately repair these genetic lesions or to remove a cell containing these lesions may result

Cellular and molecular evidence for 1,25(OH)₂D₃-independent actions of VDR selectively in keratinocytes

The disparate hair follicle and skin tumor sensitivities of the VDRKO and 1αOHaseKO mice strongly suggest that VDR has 1,25(OH)₂D₃-independent actions in skin. Until recently however, cellular and molecular data supporting this hypothesis have been lacking. We explored the transcriptional activation potential of VDR in a well-defined primary human keratinocyte cell culture system using the highly responsive 24-OHase promoter-luciferase reporter gene construct. Importantly, this is a serum-free

Summary

The stark phenotypic differences between the receptor and ligand knockout mice indicate that the actions of VDR and 1,25(OH)₂D₃ are uncoupled in the skin. The data obtained in primary human and mouse keratinocyte cultures [38] provide important cell-based, in vitro evidence supporting the in vivo phenotypic differences characterized in the VDRKO and 1αOHaseKO skin. They further indicate that VDR may control gene expression in keratinocytes independent of the 1,25(OH)₂D₃ ligand. Several

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Much of the research attributed to redox biology involving CYP-enzymes has focused on other members of the P450 family. However, the effects of these enzymes could explain some of the non-genomic changes stipulated for CYP27B1, particularly as it pertains to vitamin D activity [43–45]. A study by Favus et al. in 1986 observed similar non-genomic-effect findings in kidney proximal tubules where 25(OH)D-induced changes in metabolism and mitochondrial function, leading the authors to hypothesize these were CYP27B1-mediated effects [43].
Vitamin D deficiency has been associated with increased risk for aggressive prostate cancer (PCa). Prostate epithelium has a unique metabolism compared to other tissues. Normal prostate exhibits low levels of mitochondrial respiration and there is a metabolic switch to increased oxidative phosphorylation in PCa. 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D and is used clinically to determine vitamin D status. Activation of 25(OH)D to the transcriptionally active form, 1,25(OH)₂D occurs via a reduction-oxidation (redox) reaction within the mitochondria that is catalyzed by the P450 enzyme, CYP27B1. We sought to determine if hydroxylation of 25(OH)D by CYP27B1 contributes to non-genomic activity of vitamin D by altering the redox-dependent state of the mitochondria in benign prostate epithelial cells. Exposure to 25(OH)D produced a transient pro-oxidant effect and change in mitochondrial membrane potential that was dependent on CYP27B1. Extended exposure ultimately suppressed mitochondrial respiration, consistent with a protective effect of 25(OH)D in supporting benign prostate metabolism. To model physiologically relevant changes in vitamin D, cells were cultured in constant 25(OH)D then changed to high or deficient concentrations. This model also incurred a biphasic effect with a pro-oxidant shift after short exposure followed by decreased respiration after 16 h. Several genes involved in redox cycling and Mitochondrial Health were regulated by 25(OH)D in these cells. These results indicate a secondary non-genomic mechanism for vitamin D to contribute to prostate cell health by supporting normal mitochondrial respiration.
Alternative splicing of the vitamin D receptor modulates target gene expression and promotes ligand-independent functions
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No gain-of-function or constitutively-active splice variants arising from the class II NR family are reported, which includes the thyroid hormone receptor (TR), retinoic acid receptor (RAR) and the VDR, among others. However, multiple mechanisms underlying the known, ligand-independent functions of class II NRs, including the VDR (Castillo et al., 1999; Skorija et al., 2005; Dowd and MacDonald, 2010; Malloy and Feldman, 2013; Bikle et al., 2015; Lee and Pike, 2015) and the thyroid hormone receptor (TR) (Moriyama et al., 2016; Cvoro et al., 2016; Takamizawa et al., 2018), have been proposed. Phosphorodiamidate morpholino oligomers (PMO) whose sequences have identity with nucleic acid sequences near the splice acceptor (SA) or splice donor (SD) site of exon 8 of the human VDR mRNA were designed based on the manufacturer's recommendations.
Alternative splicing modulates gene function by creating splice variants with alternate functions or non-coding RNA activity. Naturally occurring variants of nuclear receptor (NR) genes with dominant negative or gain-of-function phenotypes have been documented, but their cellular roles, regulation, and responsiveness to environmental stress or disease remain unevaluated. Informed by observations that class I androgen and estrogen receptor variants display ligand-independent signaling in human cancer tissues, we questioned whether the function of class II NRs, like the vitamin D receptor (VDR), would also respond to alternative splicing regulation. Artificial VDR constructs lacking exon 3 (Dex3-VDR), encoding part of the DNA binding domain (DBD), and exon 8 (Dex8-VDR), encoding part of the ligand binding domain (LBD), were transiently transfected into DU-145 cells and stably-integrated into Caco-2 cells to study their effect on gene expression and cell viability. Changes in VDR promoter signaling were monitored by the expression of target genes (e.g. CYP24A1, CYP3A4 and CYP3A5). Ligand-independent VDR signaling was observed in variants lacking exon 8, and a significant loss of gene suppressor function was documented for variants lacking exon 3. The gain-of-function behavior of the Dex8-VDR variant was recapitulated in vitro using antisense oligonucleotides (ASO) that induce the skipping of exon 8 in wild-type VDR. ASO targeting the splice acceptor site of exon 8 significantly stimulated ligand-independent VDR reporter activity and the induction of CYP24A1 above controls. These results demonstrate how alternative splicing can re-program NR gene function, highlighting novel mechanisms of toxicity and new opportunities for the use of splice-switching oligonucleotides (SSO) in precision medicine.
Intake of 25-hydroxyvitamin D3 reduces duration and severity of upper respiratory tract infection: A randomized, double-blind, placebo-controlled, parallel group comparison study
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This study aimed to assess the effect of 25-hydroxyvitamin D3 (25OHD) which is a hydroxide of vitamin D3 ingestion on upper respiratory tract infection (URTI).
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Four hundred twenty eight participants aged 45-74 years were screened by their serum 25-hydoroxyvitamin D concentration.
The participants were randomized to either 25OHD (10 Î¼g/day) or placebo capsule, daily, for 16 consecutive weeks.
The primary outcome measure was the incidence proportion of URTI, and the secondary outcome measures were the physical severity score, the quality-of-life (QOL) score, the duration of URTI, and the incidence proportion of new URTI events every four weeks. Data were collected using cold diary Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) during the intervention.
Of 428 participants screened, 252 with serum 25-hydroxyvitamn D levels were deficient or insufficient (75 nmol/L or less) were enrolled in this study. Of these, 105 placebo and 110 25OHD group subjects completed the study. For the incidence proportion of URTI, no effect of 25OHD intake was observed. On the other hand, the duration of URTI was shorter in the 25OHD (P = 0.061) compared to placebo. For the incidence proportion of URTI every four weeks, the incidence of new URTI was decreased in both groups over the time of intake. However, when the 25OHD and the placebo were compared, a decrease in the incidence proportion of URTI was seen earlier in the 25OHD. When the total physical severity score and the total QOL score during the study were assessed, they both were significantly improved in the 25OHD compared to placebo.
The intake of 25OHD may reduce the duration of URTI, the physical severity, and the QOL when suffering from URTI.
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Vitamin D is the major regulator of calcium homeostasis in the body and is critically important for normal mineralization of bone to prevent rickets in children and osteomalacia in adults. The active hormone, 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃, also called calcitriol), is produced by sequential hydroxylations of vitamin D in the liver (25-hydroxylation) and the kidney (1α-hydroxylation). 1,25(OH)₂D₃ acting via the vitamin D receptor (VDR), functions by a genomic mechanism similar to the classical steroid hormones to regulate target gene transcription. The traditional actions of 1,25(OH)₂D₃ are to enhance calcium and phosphate absorption from the intestine in order to maintain normal mineral concentrations in the circulation and to provide adequate amounts of these minerals to the bone-forming sites to allow mineralization of bone to proceed normally. However, since the early 1990s, it has become increasing clear that vitamin D has many additional extraskeletal functions that implicate the hormone in a wide array of actions unrelated to bone or mineral metabolism. It is now known that 1,25(OH)₂D₃ modulates the activity of hundreds, if not thousands, of genes in essentially every tissue in the body making it a potent regulator of many critical processes. Some of these actions can be categorized as antiproliferative, prodifferentiating, immunosuppressive, and anti-inflammatory. In this chapter, we will describe the basic biology of vitamin D including its metabolism, physiology, mechanism of action, and its diverse functions in the body including those actions that relate to mineral metabolism as well as the newer extraskeletal actions. Several reviews of vitamin D mechanism of action and function have been published as well as a new edition of a comprehensive book addressing all areas of vitamin D biology. Specific issues relating to vitamin D and osteoporosis are discussed in Chapter 73.
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Citation Excerpt :
Hereditary vitamin D–resistant rickets is a rare genetic disorder caused by mutations in the VDR.84,85 Some of these patients develop alopecia, highlighting a role for VDR in normal hair follicle cycling and function.84,85 Patients with alopecia areata (AA) and alopecia universalis have not only VDR mutations but also lower 25(OH)D levels, which together inhibit proliferation and differentiation of hair follicles and epidermal cells.78,86
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^☆: Special issue selected article from the 14th Vitamin D Workshop held at Brugge, Belgium on October 4–8, 2009.

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The 1,25-dihydroxyvitamin D3-independent actions of the vitamin D receptor in skin☆

Abstract

Section snippets

The vitamin D endocrine system

Mouse knockout models point to novel mechanisms of VDR in the skin

VDR and skin, potential interplays with Hairless

VDR protects against chemically induced skin tumorigenesis

VDRKO mice are highly susceptible to UV-induced skin tumorigenesis

Cellular and molecular evidence for 1,25(OH)2D3-independent actions of VDR selectively in keratinocytes

Summary

Vitamin D: more than a “bone-a-fide” hormone

Mol. Endocrinol.

Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets

Science

Current understanding of the molecular actions of vitamin D

Physiol. Rev.

Cloning and expression of full-length cDNA encoding human vitamin D receptor

Proc. Natl. Acad. Sci. U.S.A.

Molecular cloning of complementary DNA encoding the avian receptor for vitamin D

Science

The RXR heterodimers and orphan receptors

Cell

Minireview: nuclear receptor coactivators—an update

Endocrinology

Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D

Mol. Endocrinol.

Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia

Proc. Natl. Acad. Sci. U.S.A.

Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects

Proc. Natl. Acad. Sci. U.S.A.

Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning

Nat. Genet.

Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets

Endocrinology

Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction

Proc. Natl. Acad. Sci. U.S.A.

Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses

Endocrinology

Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice

Endocrinology

Targeting expression of the human vitamin D receptor to the keratinocytes of vitamin D receptor null mice prevents alopecia

Endocrinology

Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice

Endocrinology

Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice

J. Clin. Invest.

Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1)

Bone

Ligand-independent actions of the vitamin D receptor maintain hair follicle homeostasis

Mol. Endocrinol.

The 1,25-dihydroxyvitamin D₃-independent actions of the vitamin D receptor in skin☆

Cellular and molecular evidence for 1,25(OH)₂D₃-independent actions of VDR selectively in keratinocytes