Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have compared the actions of calcitriol and its three synthetic analogs, 20-epi-22-oxa-24a,26a,27a-trihomo-1 alpha,25-dihydroxyvitamin D3 (KH 1060), 1 alpha,24S-(OH)2-22-ene-26,27-cyclopropyl vitamin D3 (MC 903) and 20-epi-1 alpha,25-dihydroxyvitamin D3 (MC 1288), on the expression of two marker genes of differentiated osteoblasts, namely alkaline phosphatase and osteocalcin, using human MG-63 osteosarcoma cells. Calcitriol and the analogs had qualitatively similar stimulatory effects on target-gene activation. Quantitatively, MC 903 behaved in most experiments essentially as the parent compound calcitriol. In vitamin D receptor/DNA complex formation MC 903, however, was more potent than calcitriol. In contrast, the 20-epi analogs, KH 1060 and MC 1288, were much more potent even at lower concentrations, than calcitriol and MC 903 in stimulating alkaline phosphatase activity, osteocalcin mRNA synthesis and osteocalcin secretion. The stimulation occurred to a greater degree and for a longer period than with calcitriol. This effect was apparently mediated by stronger and longer lasting binding of the vitamin D receptor to the osteocalcin vitamin D responsive element by the 20-epi analogs. After a 6-h treatment and during subsequent culture without hormone, the effects of the 20-epi analogs were also stronger and lasted longer than those with calcitriol or MC 903. Collectively, at comparable and lower concentrations, the 20-epi analogs, KH 1060 and MC 1288, mediate much stronger and longer lasting stimulatory effects than calcitriol or its analog MC 903 on target-gene expression associated with the differentiated phenotype of the MG-63 human osteosarcoma cells.
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PMID:Synthetic 20-epi analogs of calcitriol are potent inducers of target-gene activation in osteoblastic cells. 866 57

Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to allelic variation in the vitamin D receptor (VDR) gene. We examined allelic influences of the VDR gene on bone turnover and density in 202 normal healthy premenopausal Japanese women (age 30.1 +/- 1.2, mean +/- SEM). The VDR effect on BMD and turnover is similar to that observed in Caucasian women; however, there are major differences in allele frequency. The B allele by BsmI restriction fragment length polymorphisms (RFLPs), associated with low BMD and high bone turnover, is found in only 12% of Japanese women (1.4% homozygote BB), compared with 41% of Caucasians (16.7% homozygote BB). In comparing the two most frequent genotypes, Bb heterozygotes (21.5%) and bb homozygotes (77.1%), BMD is 5.3% lower in Bb heterozygotes, and levels of bone formation markers including osteocalcin and bone-specific alkaline phosphatase are 20-32% higher with lower serum calcium (2.30 +/- 0.02 vs 2.35 +/- 0.01 mmol/l) and higher 1,25-dihydroxyvitamin D (95 +/- 4.8 vs. 76 +/- 3.8 pmol/l). Further discrimination of the genotype was achieved using two additional RFLPs (ApaI, A and TaqI, T); the lumbar spine BMD of the common genotype BbAATt was 9.3% (0.94 SD) lower than in the bbaaTT genotype in premenopausal Japanese women. These data confirm that VDR RFLPs affect bone mineral metabolism regardless of racial differences. Moreover, the VDR genotypes based on haplotype analysis should yield useful insights into the potential prevention of osteoporosis.
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PMID:Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. 907 94

The actions of the hormonal form of vitamin D, 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25-(OH)2 D3], are mediated by both genomic and nongenomic mechanisms. Several vitamin D synthetic analogs have been developed in order to identify and characterize the site(s) of action of 1 alpha, 25-(OH)2D3 in many cell types including osteoblastic cells. We have compared the effects of 1 alpha, 25-(OH)2D3 and a novel 1 alpha, 25-(OH)2D3 bromoester analog (1,25-(OH)2-BE) that covalently binds to vitamin D receptors. Rat osteosarcoma cells that possess (ROS 17/2.8) or lack (ROS 24/1) the classic intracellular vitamin D receptor were studied to investigate genomic and nongenomic actions. In ROS 17/2.8 cells plated at low density, the two vitamin D compounds (1 x 10(-8) M) caused increased cell proliferation, as assessed by DNA synthesis and total cell counts. Northern blot analysis revealed that the mitogenic effect of both agents was accompanied by an increase in steady-state osteocalcin mRNA levels, but neither agent altered alkaline phosphatase mRNA levels in ROS 17/2.8 cells. ROS 17/2.8 cells responded to 1,25-(OH)2-BE but not the natural ligand with a significant increase in osteocalcin secretion after 72, 96, 120, and 144 hr of treatment. Treatment of ROS 17/2.8 cells with the bromoester analog also resulted in a significant decrease in alkaline phosphatase-specific activity. To compare the nongenomic effects of 1 alpha, 25-(OH)2D3 and 1,25-(OH)2-BE intracellular calcium was measured in ROS 24/1 cells loaded with the fluorescent calcium indicator Quin 2. At 2 x 10(-8) M, both 1 alpha,25-(OH)2D3 and 1, 25-(OH)2-BE increased intracellular calcium within 5 min. Both the genomic and nongenomic actions of 1,25-(OH)2-BE are similar to those of 1 alpha,25-(OH)2D3, and since 1,25-(OH)2-BE has more potent effects on osteoblast function than the naturally occurring ligand due to more stable binding, this novel vitamin D analog may be useful in elucidating the structure and function of cellular vitamin D receptors.
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PMID:Effects of the vitamin D3 analog 1 alpha, 25-dihydroxyvitamin D3-3 beta-bromoacetate on rat osteosarcoma cells: comparison with 1 alpha, 25-dihydroxyvitamin D3. 891 81

Whether vitamin D receptor gene (VDRG) polymorphism can be used as a predictor for bone turnover rate or bone mass remains controversial. Its role within various ethnic populations are also unsettled. We examined VDRG polymorphism using restrictive enzymes Bsm-I, Apa-I, and Taq-I in 155 men aged 22-88 and 113 premenopausal women aged 40-53. The bone mineral density (BMD) of the vertebrae (L2-4), proximal femur, and total body bone mineral content (tb-BMC) (women only), as well as urinary N-terminal crosslinked fragment of type I collagen (NTX), serum osteocalcin, bone isozyme of alkaline phosphatase, and caboxyterminal propeptide of type I procollagen levels were measured. Chinese men and women exhibited a low prevalence for B (absence of Bsm-I restriction site) phenotypes than white and Japanese. Within the tested samples there were 0.4% BB homozygotes, 6.7% Bb heterozygotes, and 93% bb homozygotes. The distributions of Apa-I polymorphism (9.0% AA, 42.5% Aa, and 48.5% aa) also differed from those reported for the white populations. Most of the Chinese men and women were TT homozygous (96.6%). A comparison of actual values and values adjusted for age and weight of tb-BMC and BMD at the lumbar spine, Trochanter, Ward's triangle, and femoral neck showed no significant difference among three subgroups in each of the three sets of polymorphism. Furthermore, the actual values and adjusted values (adjusted for age) of the four bone markers, respectively, showed no significant differences. We conclude that given the very low prevalence of the suspected high risk genotypes (B, A, and t), and the lack of difference among the polymorphic subgroups, VDRG polymorphism may not be an important determinant of the bone turnover rate and bone mass of Chinese men and women.
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PMID:Bone mineral density and bone markers in relation to vitamin D receptor gene polymorphisms in Chinese men and women. 892 51

In this paper, we detail an enzyme-linked immunoassay for the 1,25-dihydroxyvitamin D3 receptor protein. The receptor protein of cell and tissue homogenates is bound between two monoclonal antibodies specific for different epitopes on the receptor protein. The first antibody is bound to the well of an ELISA plate and the second is biotinylated. The receptor-antibody complex is detected with avidin-alkaline phosphatase and rho-nitrophenyl phosphate. The amount of receptor in each sample is determined by comparison with a standard curve made from purified receptor protein. This assay is highly sensitive, measuring as little as 2 fmol of receptor, and has an intra-assay coefficient of variation of 6.6% and an interassay coefficient of variation of 13.8%. The assay can be used to measure the receptor from mammalian and avian species and is independent of the presence of hormone. By eliminating the need for a radio-iodinated monoclonal antibody and incorporating the ease of a plate assay, we have a significantly improved method for measuring the vitamin D receptor protein. This paper also presents Western analysis of the antibodies used to demonstrate that they do not recognize other steroid hormone receptors.
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PMID:An enzyme-linked immunoassay for the 1,25-dihydroxyvitamin D3 receptor protein. 897 Aug 94

Polymorphisms at the vitamin D receptor (VDR) gene have been reported to mediate important differences in bone mineral density (BMD) and bone metabolism. In this longitudinal study we examined the relationships between VDR genotypes and bone metabolism, changes in BMD and changes in ultrasound transmission velocity in a population of healthy unrelated German women. The study population comprised 50 physically active women (aged 43.3 to 62.8 years, 14 premenopausal, 36 postmenopausal) with a daily calcium intake of (mean +/- SD) 1045 +/- 338 mg, who had earlier participated in a longitudinal study on the association of physical activity and bone density and bone turnover. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. Markers of bone turnover (alkaline phosphatase, osteocalcin, procollagen type I C-terminal propeptide, collagen type I C-terminal telopeptide, tartrate-resistant acid phosphatase) were measured at baseline. BMD (determined by peripheral quantitative computed tomography at the distal radius) and ultrasound transmission velocity through bone (at calcaneus, patella and thumb) were analysed at baseline and 15 months later. The genotypic groups did not differ significantly (p > 0.05) in any of the parameters determined at baseline. Neither were there any differences between these groups in the changes of BMD or ultrasound transmission velocity during the study period. Thus, we conclude that in physically active German women with a relatively high calcium intake the impact of VDR genotypic polymorphisms on bone density, bone metabolism and changes in bone density may be of limited importance.
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PMID:Vitamin D receptor genotypes and changes of bone density in physically active German women with high calcium intake. 913 41

An association between vitamin D receptor (VDR) gene polymorphisms and bone mass variance has been observed in adult populations. To analyze possible association between VDR genotype and growth, we studied 589 healthy infants who were homogeneous for age, diet, and vitamin D status. The Bsm I, TaqI, and ApaI alleles' frequencies and genotypes were similar to those reported for Caucasian populations. Variations in Bsm I polymorphism were not associated with calcium intakes nor with serum levels of calcium, 25-hydroxyvitamin D, 1, 25-dihydroxyvitamin D, or alkaline phosphatase activity. But, they were associated with differences in body size. At 2 yr, homozygote BB (BsmI site absent) girls had higher length, weight and body surface area, and inversely, BB boys had lower weight, body mass index and body surface area, than their respective bb counterparts. As a result, gender-related differences were observed in Bb and bb, but not in BB populations. This VDR genotypic effect was observed also at birth and at 10 months in the longitudinal analysis of 145 selected full-term babies homozygous for the Bsm I polymorphism. These findings provide support for the hypothesis that VDR genotype influences intrauterine and early postnatal growth, directly or via interactions with gender-related growth regulators.
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PMID:Association between vitamin D receptor gene polymorphism and sex-dependent growth during the first two years of life. 928 28

Recent advances in molecular and cellular biology have contributed significantly to the elucidation of the pathogenesis of many kinds of skeletal dysplasia. The number of skeletal dysplastic diseases that are identified to have associated abnormalities in genes has increased. Some diseases such as achondroplasia, thanatophoric dysplasia and hypochondroplasia are shown to be allelic. In addition to those diseases associated with mutations of the fibroblast growth factor receptor 3 gene, the abnormalities in collagen, Gs alpha, vitamin D receptor and tissue nonspecific alkaline phosphatase genes are briefly reviewed in this article.
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PMID:Recent advances in molecular analysis of skeletal dysplasia. 931 99

Several studies have shown that bone mass and bone turnover are genetically determined. This genetic component is thought to be mediated in part by polymorphisms at the vitamin D receptor (VDR) locus, even though the underlying molecular mechanisms are still unknown. To evaluate a possible site of differential action of the VDR gene alleles we examined their correlation with intestinal calcium absorption in 120 Caucasian postmenopausal women (aged 61 +/- 0.6 years). VDR gene polymorphisms for Apa I, Bsm I, and Taq I restriction endonucleases were assessed by Southern blotting analysis. The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%). Although there was some evidence of 13% higher lumbar BMD values in aabbTT genotype with respect to AABBtt genotype, this difference of approximately 0.1 g/cm2 did not reach statistical significance, possibly because of the limited number of observations. On the contrary, no relationship was found between genotypes and femoral neck BMD values. Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotypes (P = 0.0015 ANOVA). No significant differences in intact PTH, alkaline phosphatase, 25OHD3, and 1, 25(OH)2D3 were found among subjects with different VDR genotypes. These results are consistent with a possible role of VDR alleles on intestinal calcium absorption.
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PMID:Vitamin D receptor genotypes and intestinal calcium absorption in postmenopausal women. 938 72

Growth plate cartilage cell express receptors for, and are affected by both IGF-I and 1 alpha, 25(OH)2D3. The studies were undertaken to investigate interaction between these two hormone systems, that is, (i) to study effects of 1 alpha, 25(OH)2D3 on IGF-type 1 receptors (IGFIR), on IGF-I stimulated cell replication, colony formation, and on alkaline phosphatase activity (AP), and conversely, (ii) to study the effect of IGF-I on vitamin D receptor (VDR) expression on 1 alpha, 25(OH)2D3 stimulated growth parameters and on AP activity. Freshly isolated rat tibial chondrocytes were grown in monolayer cultures, (serum-free) or in agarose stabilized suspension cultures (0.1% FCS). Vitamin D receptor and IGFIR were visualized by immunostaining with the monoclonal antibody (mAb) 9A7 gamma and mAb alpha IR3, respectively, and quantitated by RT-PCR for mRNA and by Scatchard analysis using [3H]-1,25(OH)2D3 and [125I]-alpha IR3. Cell proliferation was measured by [3H]-thymidine incorporation, growth curves in monolayer cultures, and by colony formation in agarose-stabilized suspension cultures. IGF-I dose-dependently increased [3H]-thymidine incorporation. 1 alpha, 25(OH)2D3, but not 1 beta, 25(OH)2D3 was stimulatory at low ((10-12 M) and slightly inhibitory at high (10-8 M) concentrations. The effect of IGF-I was additive to that of 1 alpha, 25 (OH)2D3 [IGF-I 60 ng/ml, 181 +/- 12.7; 1 alpha, 25(OH)2D3 10(-12) M, 181 +/- 9.8%, IGF-I + 1 alpha, 25(OH)2D3, 247 +/- 16.7%, P < 0.05 by ANOVA] and specifically obliterated by polyclonal IGF-I antibody (AB-1). Interaction could also be confirmed in suspension cultures. IGFIR mRNA and [125I]-alphaIR3 binding was increased by low (10(-12) m) but not by high (10(-8) M) concentrations of 1 alpha, 25(OH)2D3. Homologous up-regulation by IGF-I (60 ng/ml) was specifically inhibited by AB-1 and markedly amplified by coincubation with 1 alpha, 25(OH)2D3 (10(-12)m). Immunostaining with alpha IR3 showed specific IGFIR expression in rat growth cartilage, but not liver tissue. Stimulation of chondrocytes with 1 alpha, 25(OH)2D3 or IGF-I suggested some increase of receptor expression in single cells, but the predominant effect was increased recruitment of receptor positive cells, Vitamin D receptor expression was markedly stimulated (fourfold) by IGF-I (60 ng/ml), but not IGF-II and inhibited by actinomycin D. This study shows that IGF-I and 1 alpha, 25(OH)2D3 mutually up-regulate their respective receptors in growth plate chondrocytes. In parallel, they have additive effects on cell proliferation and colony formation suggesting independent effector pathways.
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PMID:Interaction of IGF-I and 1 alpha, 25(OH)2D3 on receptor expression and growth stimulation in rat growth plate chondrocytes. 957 29


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