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At least 127 records · Page 7Linked to original sources
PubMed2002

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

BACKGROUND: Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear. AIM: To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes. DESIGN: Prospective cross-sectional, interventional and embedded studies. METHODS: Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis. RESULTS: Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.

Adult↗
PubMed2006

VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a secosteroid hormone that regulates bone metabolism, controls calcium homeostasis, and possesses immunomodulatory properties. We show here that 1,25(OH)2D3 contributes to the regulation of development and function of mast cells, which play a critical role in several inflammatory disorders. 1,25(OH)2D3 promotes apoptosis and inhibits maturation of mouse bone marrow-derived mast cell precursors. Dose-dependent inhibition of mast cell differentiation by 1,25(OH)2D3 is observed at discrete, intermediate stages of mast cell development, identified by expression of c-kit, FcepsilonRI, and IL-3 receptor-alpha chain, and depends on the expression of the vitamin D receptor (VDR). It is important that mast cell progenitors obtained from VDR-ablated mice undergo an accelerated maturation in vitro and give rise to more responsive mast cells than wild-type. Furthermore, histological analysis of mast cell density in peripheral tissues reveals a moderate increase in the number of mast cells in the skin of VDR-deficient mice compared with wild-type animals. These data support the hypothesis of a physiological role of 1,25(OH)2D3 in mast cell development and suggest novel, therapeutic uses of 1,25(OH)2D3 analogs.

Animals↗
PubMed2006

Recent results on A-ring modification of 1alpha,25-dihydroxyvitamin D3: design and synthesis of VDR-agonists and antagonists with high biological activity.

The structure-activity relationships of 1alpha,25-dihydroxyvitamin D3 on simultaneous modification at both C2alpha and CD-ring side chain, including 20-epimerization, double side chain (gemini), and vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 lactone rings, and also on simultaneous modifications at both C2 and C10 positions, i.e., C2 modified active 19-norvitamin D3, have been studied in our laboratory to find new seeds of B-seco-steroidal medicine for treating bone diseases, psoriasis, secondary hyperparathyroidism, and certain kinds of cancers. We developed an efficient and systematic route to the 2alpha-substituted 1alpha,25-dihydroxyvitamin D3 analogs, i.e., VDR-agonists (20-epi-2-4, double side chain 13a-c, 19-nor 15a-c) and antagonists (36a-c, 37a-c). The A-ring precursors (11a-o) for these analogs were synthesized from D-glucose as a chiral template. In the 19-nor series, we used radical coupling reaction for preparing the A-ring parts from (-)-quinic acid, and the resulting 2-substituted A-ring moiety was coupled with 25-hydroxy Grundmann's ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2alpha-functional group to the TEI-9647 and TEI-9648 skeletons.

Calcitriol↗
PubMed2004

VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study.

OBJECTIVE: To explore the potential role of vitamin D receptor (VDR) gene and natural-resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms in susceptibility to pulmonary tuberculosis (PTB) in the Chinese Han population. DESIGN: In an unmatched case-control study, 120 well defined PTB patients and 240 unrelated normal controls were enrolled. Information on potential risk factors of PTB was collected using a standard questionnaire. Genetic polymorphisms of VDR gene (TaqI and FokI) and NRAMP1 gene (INT4, D543N and 3'UTR) were analysed using PCR and RFLP. Unconditional logistic regression was performed, and odds ratios (ORs), their 95% confidence intervals (CI) and P values were estimated using maximum likelihood methods. RESULTS: Univariate analysis demonstrated that FokI-ff homozygotes, D543N G/A and 3'UTR TGTG+/del heterozygotes occurred more frequently in patients than in controls. The crude ORs were 2.345 (95%CI 1.222-4.499), 2.590 (95%CI 1.043-6.434) and 1.890 (95%CI 1.171-3.051), respectively, compared with their corresponding common genotypes. The P values were 0.033, 0.041 and 0.030, respectively. After adjusting for exposure history and BCG immunisation in the multivariate analysis, the adjusted ORs were 4.625 (95%CI 1.737-12.312), 2.415 (95%CI 1.079-8.759) and 2.187 (95%CI 1.146-4.175), with P values of 0.002, 0.036 and 0.018, respectively. Neither univariate nor multivariate analysis disclosed any significant association between the disease and TaqI or INT4. CONCLUSIONS: Polymorphisms in the VDR and NRAMP1 gene are statistically associated with susceptibility to PTB in the Chinese Han population.

Adult↗
PubMedDate not supplied

Vitamin-D receptor (VDR) gene (Fok-I, Taq-I and Apa-I) polymorphisms in healthy individuals from north Indian population.

The vitamin-D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of immune responses, and regulation of cell proliferation and differentiation. Variation in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular ailments, urolithiasis and tuberculosis. Activity of Vit-D is mediated by the vitamin D receptor (VDR), a ligand dependent receptor. VDR gene polymorphisms thus represent strong positional candidates for different diseases like prostate cancer, urolithiasis, inflammatory bowl disease and osteoporosis. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and can reveal modest and subtle but true biological effects. The abundance of polymorphisms in the human genome as well as high frequencies in human populations have made them targets to explain variation in risk of common diseases. The present study was carried out to determine the distribution of VDR gene (Fok-I, Taq-I and Apa-I) polymorphisms using a PCR-based restriction analysis in unrelated normal healthy individuals from a north Indian population. We obtained allelic frequencies of (68.5% vs 31.5%), (66% vs 34%) and (58% vs 42%) for (F vs f), (T vs t) and (A vs a) alleles, with 44%, 49% and 7%, respectively, for genotypes FF, Ff and ff , 49%, 40% and 11% for TT, Tt and tt and 36%, 44% and 20% for AA, Aa and aa. Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from in other populations and ethnic groups. Thus the data signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.

Adolescent↗
PubMedDate not supplied

Polymorphism of VDR gene--the most effective molecular marker of osteoporotic bone fractures risk within postmenopausal women from Wielkopolska region of Poland.

The major public health problem which will arise is a frequency of osteoporosis. The first manifestations of this disease are often bone fractures. Identification and evaluation of individual bone fracture risk will be the most effective way of solving the problem. Genetic determination of osteoporosis is unquestionable. The aim of this study is to detect which variants of genotypes lead to illness. We investigated 187 patients with osteoporosis (161 women, 26 men) and 19 healthy subjects. Polymorphisms of the following genes were investigated: OPG, VDR, ESR1, TGFB1 COL1A1, and BMP2. The statistically significant relationship between BMD value and T allele of Taq I VDR gene were found. Genotypes: aa, bb, TT of VDR gene occur more frequently in polish osteoporotic population in Wielkopolska region within patients with higher risk of bone fractures.

Aged↗
PubMed2002

Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population.

Low bone mineral density (BMD) is a major risk factor for the development of osteoporosis and there is strong evidence to suggest that the procurement and preservation of peak BMD is genetically determined. In an effort to identify factors responsible for susceptibility to low BMD in the Irish population, we investigated its possible association with polymorphisms in the Osteoprotegerin (OPG) gene, Type I collagen alpha 1 (COLIA1) Sp1 binding site and vitamin D receptor (VDR) start codon. Following a systematic screening of the regulatory and coding regions of the OPG gene, we identified a novel G1181C polymorphism in exon 1 and a T950C polymorphism in the promoter region of the OPG gene. Participants were recruited from the Bone Densitometry Unit of Cork University Hospital, including 381 postmenopausal women aged 61.26 +/- 8.50 (mean +/- SD) and 130 premenopausal women aged 46.30 +/- 6.50 (mean +/- SD). Following association analysis using both the premenopausal and postmenopausal cohorts we found that postmenopausal women carrying one or more C alleles of the G1181C polymorphism had 14.8% lower BMD (P = 0.05) at the lumbar spine and 14.4% lower BMD (P = 0.04) at the FN. However, both were nonsignificant when the Bonferroni correction factor (0.01 significance level) was applied to correct for multiple hypothesis testing. We found no association between alleles of the T950C OPG polymorphism and BMD. Similarly, we have found a lack of association between the VDR (fok1) polymorphism or COLIA1 Sp1 polymorphism and low BMD in either postmenopausal or premenopausal women in this population.

Base Sequence↗
PubMed2006

New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations.

We have successfully prepared E- and Z- isomers of 17-20 dehydro analogs of 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD). Both isomers bind to the recombinant rat vitamin D receptor (VDR) with high affinity. The Z-isomer (Vit-III 17-20Z) displays activity in vivo and in vitro that is similar to 2MD. The in vitro activity of the E-isomer (Vit-III 17-20E) is comparable to the natural hormone, though in vivo this analog is significantly less calcemic. Crystal structures of the rat VDR ligand binding domain complexed with the analogs demonstrate that the Vit-III 17-20Z analog is oriented almost identically to 2MD, with only minor differences induced by the planar configuration around the C17-C20 double bond. The Vit-III 17-20E analog is oriented in a conformation distinct from both 2MD and the natural hormone. The structural comparisons suggest that the position of C21 in the ligand binding site may be an important determinant of biological activity.

Calcitriol↗
PubMed2004

Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2.

All Vitamin D analogs possessing the A ring modified at C-2 and showing calcemic activities nest themselves in the VDR binding pocket, oriented towards Tyr 143. Such topology resembles the position of the Vitamin D hormone in hVDRmt [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491]. Conversely, inactive 2beta-methyl-19-nor-analogs anchor the receptor cavity in a distinguishably different manner, namely by their side chain. Moreover, these inactive vitamins have a different conformation around C(6)-C(7) bond. Topology of modeled complexes suggests that a Vitamin D analog will be biologically active if its intercyclic 5,7-diene moiety assumes parallel position to tryptophan aromatic rings; such orientation allows for creating pi-pi interactions. The broad comparison of calcemic activities of the analogs, and their interactions with VDR, revealed that specific hydrophobic contacts are involved in bone calcium mobilization (BCM). These contacts occur between 21-methyl group and a few amino acids (V296, L305 and L309), conserved in the nuclear receptor superfamily. In the inactive 2beta-methyl-19-nor analogs such contacts do not exist. We speculate that two hydrophobic receptor patches, being in close contact with ligand methyl groups, might influence interaction with co-modulators involved in calcium homeostasis.

Animals↗
PubMed2002

Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements.

The nuclear vitamin D receptor (VDR) mediates the effects of 1,25-dihydroxyvitamin D(3) (1,25D(3)) to alter intestinal gene transcription and promote calcium absorption. Because 1,25D(3) also exerts anti-cancer effects, we examined the efficacy of 1,25D(3) to induce cytochrome P450 (CYP) enzymes. Exposure of human colorectal adenocarcinoma cells (HT-29) to 10(-8)M 1,25D(3) resulted in >/=3-fold induction of CYP3A4 mRNA and protein as assessed by RT-PCR and Western blotting, respectively. Six vitamin D responsive element (VDRE)-like sequences in the promoter region of the CYP3A4 gene were then individually tested for their ability to enhance transcription. A canonical DR3-type element in the distal region of the promoter (-7719-GGGTCAgcaAGTTCA-7733), and a proximal, non-classical everted repeat with a spacer of 6 bp (ER6; -169-TGAACTcaaaggAGGTCA-152) were identified as functional VDREs in this CYP gene. These data suggest that 1,25D(3)-dependent, VDR-mediated induction of CYP3A4 may constitute a chemoprotective mechanism for detoxification of enteric xenobiotics and carcinogens.

Calcitriol↗
PubMed2001

Cross-talk between 1,25-dihydroxyvitamin D3 and transforming growth factor-beta signaling requires binding of VDR and Smad3 proteins to their cognate DNA recognition elements.

1,25-Dihydroxyvitamin D(3) (vitamin D) and transforming growth factor-beta (TGF-beta) regulate diverse biological processes including cell proliferation and differentiation through modulation of the expression of target genes. Members of the Smad family of proteins function as effectors of TGF-beta signaling pathways whereas the vitamin D receptor (VDR) confers vitamin D signaling. We investigated the molecular mechanisms by which TGF-beta and vitamin D signaling pathways interact in the regulation of the human osteocalcin promoter. Synergistic activation of the osteocalcin gene promoter by TGF-beta and vitamin D was observed in transient transfection experiments. However, in contrast to a previous report by Yanagisawa, J., Yanagi, Y., Masuhiro, Y., Suzawa, M., Watanabe, M., Kashiwagi, K., Toriyabe, T., Kawabata, M., Miyazono, K., and Kato, S. (1999) Science, 283, 1317-1321, synergistic activation was not detectable when the osteocalcin vitamin D response element (VDRE) alone was linked to a heterologous promoter. Inclusion of the Smad binding elements (SBEs) with the VDRE in the heterologous promoter restored synergistic activation. Furthermore, this synergy was dependent on the spacing between VDRE and SBEs. The Smad3-Smad4 heterodimer was found to bind in gel shift assay to two distinct DNA segments of the osteocalcin promoter: -1030 to -989 (SBE3) and -418 to -349 (SBE1). Deletion of SBE1, which is proximal to the VDRE, but not the distal SBE3 in this promoter reporter abolished TGF-beta responsiveness and eliminated synergistic co-activation with vitamin D. Thus the molecular mechanism, whereby Smad3 and VDR mediate cross-talk between the TGF-beta and vitamin D signaling pathways, requires both a VDRE and a SBE located in close proximity to the target promoter.

Animals↗
PubMed2006

Bone metabolism markers predict increase in bone mass, height and sitting height during puberty depending on the VDR Fok1 genotype.

OBJECTIVES: Longitudinal growth and bone mass accumulation are two important phenomena during puberty, resulting in attainment of peak bone mass (PBM) and final height. They are thought to be under strong genetic control, with the vitamin D receptor (VDR) gene being among the candidate genes. Bone metabolism markers are reported to be good predictors of longitudinal growth and bone mass increase. The purpose of this longitudinal study was to evaluate whether bone metabolism markers predict bone mass and height increase differently according to Fok1 VDR genotype throughout puberty in healthy adolescents. PATIENTS AND MEASUREMENTS: At the start of the study 130 girls were aged 10.8 (range 8.5-12.8) years and 125 boys were aged 11.8 (range 9.4-14.6) years at the first visit. Markers of bone formation and bone resorption were measured at the first visit, as well as height and sitting height (SH), and bone mineral content (BMC) of the lumbar spine, femur, arm and total body. All measurements were repeated after 2 years. RESULTS: A higher BMC of the femur, distal arm and total body was found in ff boys at the first visit, which was not related to higher levels of bone metabolism markers in this group. In girls, no differences between genotypes were seen in BMC (increase). However, concentrations of markers of bone formation [alkaline phosphatase (AP), bone-specific alkaline phosphatase (BAP), procollagen aminoterminal propeptide (PINP)] and bone resorption [type I carboxyterminal telopeptide (ICTP)] were higher in ff girls. Regression coefficients between bone metabolism markers and bone mass increase differed according to genotype and sex. A similar pattern was found for height and SH (increase), the latter as a representative of growth of the axial skeleton, mainly consisting of cancellous bone. CONCLUSIONS: Our data suggest that the predicting capacities of bone metabolism markers on bone mass (increase), height and SH (increase) are genotype dependent. Their use as predictors of final height or PBM therefore remains questionable without knowing the genotype.

Adolescent↗
PubMed1999

The independent and combined effects of RAR-, RXR-, and VDR-selective ligands on the growth of squamous cell carcinoma in vitro.

OBJECTIVE: The purpose of our study was to analyze the independent and combined effects of RAR-, RXR-, and VDR-selective ligands on the growth of squamous cell carcinoma to develop new, more effective, and less toxic chemopreventive therapy. METHOD: The effects of 13-cis retinoic acid (13-cis RA), LG1069 (a highly selective RXR ligand), and vitamin D3 (D3) were analyzed in vitro in the SCC-25 human squamous cell carcinoma cell line. SCC-25 cells were grown in culture medium containing vehicle or hormone at the indicated concentrations. Growth of surviving cells was then assessed using a hemocytometer. The presence of functional vitamin D3 receptor (VDR) was confirmed using gene-transfer experiments with a promoter-lac Z reporter plasmid. RESULTS: D3 and 13-cis RA have equipotent antiproliferative effects on SCC-25 cells. Furthermore, equimolar LG1069 completely blocks the growth-suppressive effects of D3 but has no effect on the action of 13-cis RA. CONCLUSION: D3 and its analogs, administered alone or in combination with 13-cis RA, may provide more effective and less toxic chemopreventive therapy for the prevention of second primary carcinomas of the head and neck.

Antineoplastic Agents↗
PubMed2000

[The influence of hormone replacement therapy (HRT) on bone density in menopausal women in relation to vitamin D receptor (VDR) and estrogen receptor (ER)].

The aim of the study was determination of VDR and ER alleles combination in woman with primary osteoporosis and estimation of bone mass increment after one year of estro-progestagen cyclic therapy enriched with vitamin D analogues, diet containing of calcium and regular physical exercises. The greatest mean BMD was obtained woman without detected polymorphism in VDR and ER genes.

Bone Density↗
PubMed2003

[Analysis of Bsm I polymorphism of the vitamin D receptor (VDR) gene in Venezuelan female patients living in the state of Zulia with osteoporosis].

Among genes implied on the osteoporosis genetics, the most studied gene worldwide is the receptor gene of D vitamin (VDR), through the characterization of Bsm I polymorphism. The main objective of this research was to analyze the Bsm I polymorphism of the VDR gene in a sample of 133 postmenopausal women distributed in three groups: 54 with osteoporosis, 24 with osteopenia and 55 normal controls for the disease. 28 of the women with osteoporosis presented the BB genotype, which is related in other countries to bone mineral density decrease, 20 had the Bb genotype, and 6 the bb genotype. Of the control group only 11 women presented the BB genotype, 36 showed the heterozygote genotype and 8 the bb genotype. The frequencies of the B and b alleles in the analyzed population were 0.6 and 0.4 respectively. The BB genotype was found in 52% of the group with osteoporosis, and in 20% of the control group, these findings are statistically significant, which suggest an association between the BB genotype and osteoporosis.

Female↗
PubMed2004

[VDR function in skin].

Typical abnormalities of hereditary rickets type II patients were observed in the mice deficient of VDR with growth retardation, impaired bone formation and alopecia. Except alopecia, all of the abnormalities were rescued by dietary supplement of high minerals. Genetic mutations in the critical vitamin D biosynthesis enzyme in humans and mice also suffer rachtic phenotypes except alopecia. The function of VDR in skin will be discussed.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2003

[Dietary calcium and VDR gene polymorphism's interaction].

The fundamental role of vitamin D receptor (VDR) gene polymorphisms have been reviewed. The VDR gene polymorphisms are associated with the intestinal calcium absorption , rate of bone gain and loss. The observed variability in younger and elderly people in the response of bone mass to calcium intake and supplementation may be explained partly by the interaction between environmental and genetic factors.

English Abstract↗
PubMed1991

The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7.

By means of somatic cell hybrids segregating either human or rat chromosomes, the genes encoding the transcription factor Sp1 (SP1) and the 1,25-dihydroxyvitamin D3 receptor (VDR) were both assigned to human chromosome arm 12q and to rat chromosome 7. This result implies that the locus for the clinical disorder vitamin D dependency rickets type II maps on 12q. The phenylalanine hydroxylase (PAH) and the retinoic acid receptor-gamma (RARG) genes also map on human chromosome arm 12q and rat chromosome 7, indicating that a synteny group is conserved on these chromosomes.

Animals↗