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)

Estrogen responsiveness of bone is a fundamental regulatory mechanism operative in skeletal homeostasis. We examined the expression of estrogen receptor-alpha (ER) messenger RNA (mRNA) in cultured rat calvarial-derived osteoblasts during progressive development of the osteoblast phenotype. Levels of ER message were compared with the expression of traditional osteoblastic markers that have been mapped throughout the differentiation process of these cells. ER transcripts, measured using semiquantitative RT-PCR analysis, were expressed at low levels in early stage proliferating osteoblasts and increased at confluence upon initial expression of bone cell phenotypic genes. A 23-fold up-regulation of ER mRNA expression coincided with the initiation of alkaline phosphatase activity (day 8). ER mRNA levels progressively increased 70-fold, reaching a maximum level on days 22-25 in fully differentiated osteoblasts when osteocalcin expression peaked, but declined precipitously by day 32 in osteocytic cells. Analysis of RNA isolated directly from rat calvaria confirmed these in vitro results and demonstrated that ER message levels become more abundant postnatally as bone becomes more mineralized. We also examined the responsiveness of osteoblasts to 17beta-estradiol (17beta-E2) at two periods of maturation: the nodule-forming stage (day 14) and the late mineralization stage (day 30). Estradiol suppressed the levels of alkaline phosphatase, osteocalcin, osteonectin, and ER mRNAs on day 14, but up-regulated these messages on day 30. In contrast, 17beta-E2 treatment regulated the steady state levels of transforming growth factor-beta1 and type I procollagen mRNAs only in the late mineralization stage, whereas histone H4 message was unaffected by the steroid at either stage of differentiation. Thus, the observed developmental expression of ER mRNA correlates with progressive osteoblast differentiation and may be a contributing factor to differential regulation of bone cell gene expression by 17beta-E2.
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PMID:Estrogen receptor-alpha is developmentally regulated during osteoblast differentiation and contributes to selective responsiveness of gene expression. 952 93

The effects of pregnancy and lactation on bone histomorphometry have been studied extensively in rats and dogs. However, these models differ greatly in reproductive physiology compared with women. The purpose of this study was to evaluate histomorphometric changes in iliac crest bone biopsies taken from cynomolgus monkeys (Macaca fascicularis), animals similar to women both skeletally and reproductively. After fluorochrome labeling, paired iliac crest bone biopsies were collected and subjected to structural and dynamic histomorphometric analyses during the third trimester and 3 months postpartum in one group (n=16), at 3 and 9 months postpartum in the second group (n=14), and at 4 month intervals in a nonpregnant control group (n=6). Serum was collected at the time of surgery to measure total alkaline phosphatase (ALP), bone gla-protein (BGP), calcium, and estradiol. Trabecular thickness increased significantly between 3 and 9 months postpartum. Bone formation rates did not differ between control and pregnant monkeys, but were significantly increased during lactation (3 months postpartum) and remained elevated at 9 months postpartum. ALP and BGP levels were elevated at 3 months postpartum, compared with levels during pregnancy, and remained elevated at 9 months postpartum. Estradiol concentrations were greatly elevated during pregnancy, dropped below normal nonpregnant levels by 3 months postpartum, and remained suppressed at 9 months postpartum. These results suggest that, during the third trimester, the rate of bone turnover was not altered, but lactational demands for calcium were met in part by increased bone turnover.
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PMID:Effects of pregnancy and lactation on bone in cynomolgus macaques: histomorphometric analysis of iliac biopsies. 960 Jul 90

Previous studies have shown that treatment with estrogen or calcium decreases bone turnover in older women. The mechanisms by which estrogen and calcium exert their effects are probably different. We therefore examined the possibility of an additive or synergistic effect of combined treatment with calcium and low dose estrogen on bone turnover in older women, using biochemical markers. Thirty-one healthy women over 70 yr of age were randomized to 12 weeks of treatment with either micronized 17beta-estradiol [0.5 mg/day Estrace (E2)] or 1500 mg/day elemental calcium, given as carbonate plus vitamin D (800 IU/day; Ca+D). At the end of the initial 12-week treatment period, both groups received both Ca+D and E2 for an additional 12 weeks. Eleven older women were followed for 36 weeks without any treatment and served as a control group. Serum and urine were collected at baseline, at 12 and 24 weeks on treatment, and at 12 weeks after treatment was terminated for measurement of biochemical markers of bone turnover. Markers of bone formation were bone alkaline phosphatase, osteocalcin, and type I procollagen peptide; markers of bone resorption were urinary cross-linked C-telopeptides and N-telopeptides of type I collagen, serum cross-linked N-telopeptides of type I collagen, urinary free deoxypyridinoline cross-links, and serum bone sialoprotein. Repeated measures ANOVA was used to determine changes in bone turnover measures over time by group. All markers of bone resorption decreased with initial treatment and decreased further with combination therapy (P < 0.001). Markers of bone formation decreased with Ca+D treatment, but not with E2 alone; there was no additional effect of combination therapy on formation markers compared to Ca+D alone. Neither markers of formation nor resorption changed in the control group. These results suggest that there is an additive effect of low dose estrogen and calcium on bone resorption, but not on bone formation, in older women. Thus, the combination of low dose estrogen plus calcium is likely to be more effective in older women than either treatment alone.
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PMID:Low dose estrogen and calcium have an additive effect on bone resorption in older women. 992 80

Sulfation is an important conjugation reaction in the metabolism of steroids. Steroids sulfates do not interact with the appropriate hormone receptors; additionally, the presence of the charged sulfate moiety increases the aqueous solubility and excretion of most steroids. Estrogen sulfotransferase (EST) is the major form of human cytosolic ST involved in the conjugation of estrogens. EST is important in the inactivation of beta-estradiol (E2) during the luteal phase of the menstrual cycle. EST has a significantly higher affinity for the sulfation of E2 and 17alpha-ethinylestradiol (EE2) than for other potent estrogens such as diethylstilbestrol (DES) and equine estrogens. The ability of EST to sulfate these estrogenic compounds at physiologic concentrations is important in regulating their activation of the ER in estrogen responsive cells. Human Ishikawa endometrial adenocarcinoma (ISH) cells possess an estrogen receptor (ER)-regulated alkaline phosphatase (AlkPhos) which is used to assay ER activation. To study the effects of EST activity on the ER activation of different estrogenic compounds, ISH cells were stably transformed with an EST expression vector. Dose-response curves for the induction of AlkPhos activity by the different estrogenic compounds were generated with EST/ISH and control pcDNA/ISH cells. EST/ISH cells were 200-fold less sensitive to E2 and EE2 than were control cells. No differences were observed in the dose response curves for DES between EST/ISH and pcDNA/ISH cells. EST/ISH cells were approximately 3-10-fold less sensitive to the equine estrogens equilin and 17-equilin as compared to control cells. The ability of EST to decrease the ER activation of an estrogen correlates with the sulfation of these compounds at nanomolar concentrations by EST/ISH and pcDNA/ISH ISH cells. These results indicate that EST is capable of efficiently inactivating E2 and EE2 but is significantly less effective in inhibiting the ER binding of other potent estrogenic compounds.
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PMID:Regulation of estrogen activity by sulfation in human Ishikawa endometrial adenocarcinoma cells. 1036 11

A total of 277 early postmenopausal women were enrolled in this placebo-controlled 2-year study to examine the efficacy of a matrix transdermal 17beta-estradiol system, at three different dosages (25, 50 and 75 mg/day) combined with sequential oral dydrogesterone 20 mg/day, in preventing bone loss. At 2 years, the difference from placebo in percentage change from baseline of L1-4 lumbar spine bone mineral density (BMD) (assessed by dual-energy X-ray absorptiometry) was 4.7% +/- 0.7% with estradiol 25 mg/day, 7.3% +/- 0.7% with estradiol 50 mg/day and 8.7% +/- 0.7% with estradiol 75 mg/day (all values mean +/- SEM). There were also significant increases in femoral neck, trochanter and total hip BMD with all doses of estradiol compared with placebo. Additionally, most patients had a significant gain (increase greater than 2.08%) in lumbar spine bone mass compared with placebo. Patients who received estradiol also experienced clinically significant and dose-related decreases in total serum osteocalcin, serum bone alkaline phosphatase and urinary C-telopeptide, with all three markers of bone turnover returning to premenopausal levels. Estradiol was well tolerated during the 2-year treatment period. Transdermal estradiol is effective and well tolerated at dosages between 25-75 mg/day in the prevention of bone loss in postmenopausal women; 25 mg/day offers an effective option for those women who cannot tolerate higher doses.
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PMID:Matrix delivery transdermal 17beta-estradiol for the prevention of bone loss in postmenopausal women. The International Study Group. 1055 Apr 54

Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.
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PMID:Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys. 1147 85

This 2-year, double-masked, randomized, placebo-controlled trial was designed to evaluate the safety and efficacy in preventing bone loss in postmenopausal women of two doses of transdermal 17betaestradiol (estradiol) delivered by a matrix patch, compared with placebo. One hundred and sixty healthy, hysterectomized postmenopausal volunteers aged 40-60 years with serum estradiol levels < 20 pg/ml were started on treatment at four centers in The Netherlands. Every 6 months, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, non-dominant wrist and left hip, and markers of bone turnover were assessed in urine and serum. The treatment arms were: estradiol, 100 microg/day (E-100, n = 53), oestradiol, 50 microg/day (E-50, n = 54), placebo (P-100, placebo to E-100, n = 27 or P-50, placebo to E-50, n = 26). Treatment was continued for up to 2 years. After 24 months, BMD of the lumbar spine in the E-100 group differed by 7.7% [5.8-9.5%] (mean [95% confidence interval]) from the placebo group and showed a mean (s.e.m.) increase in BMD from baseline of 5.9% (0.69%). For the E-50 group the difference compared with placebo was 6.2% [4.4-8.0%] and the absolute increase was 4.5% (0.62%); in the placebo group, the absolute change was -2.3% (0.48%). In the total wrist, the changes were: E-100: difference compared with placebo 2.5% [1.5 3.6%], absolute increase 0.6% (0.3%); E-50: difference compared with placebo 2.9% [1.8-3.9%], absolute increase 0.7% (0.25%); and absolute change on placebo: -2.5% (0.35%). In the total hip, the changes were: E-100: difference compared with placebo 3.7% [2.2-5.2%], absolute increase 2.8% (0.5%); E-50: difference compared with placebo: 3.2% [1,8-4.7%], absolute change 2.4% (0.36%); and absolute change on placebo -1.4% (0.66%). Three markers of bone turnover--serum bone-specific alkaline phosphatase, serum osteocalcin and urinary CTX--fell significantly during the trial. Breast pain was reported by 8% of women on placebo, by 6% of women on E-50 and by 17% of women on E-100. Estradiol delivered by the E-50 matrix patch effectively reversed bone loss in hysterectomized postmenopausal women with few side-effects. The marginal additional gain in BMD with the higher dose may be offset by a more important side effect profile.
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PMID:Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial. 1190 92

The commutability of 13 control materials was evaluated by performing parallel measurements on two different analysers: a Synchron CX-5 Delta from Beckman-Coulter and a Vitros 950 from Ortho-Clinical Diagnostics. Twenty three clinical chemistry analytes (substrates, electrolytes and enzymatic activities) were determined in plasma from 15 different patients in order to define intermethod relationship for each analyte. The relationship observed for each control material was compared to those obtained for patients' specimens. The results show that commutability depends both on the tested analyte and on the control material. No totally commutable material has been found for the whole set of tested parameters. Most control materials were commutable for inorganic phosphate, glucose, chloride, triglycerides, alanine aminotransferase, amylase and y-glutamyltransfera-se, but less than a quarter of control materials were commutable for sodium, calcium, creatinine, alkaline phosphatase and lipase. Seven materials were commutable for more than half of the analytes, whereas five control materials were commutable for less than a quarter of these analytes. We propose to verify the commutability of materials before their use in an external quality control assessement.
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PMID:Evaluation of commutability of control materials. 1221 60

To investigate day-to-day biological change of biochemical makers of bone turnover, we measured eight markers for 5 days in 10 healthy women. They aged 26-41 years (mean age; 31.1 years old), and had regular menstrual cycles. Fasting second void urine and blood was collected from them on five successive days. As serum marker, Estradiol (E2), intact PTH (i-PTH), Bone-specific alkaline phosphatase (BAP), and serum C-telopeptide (S-CTX) were measured. As urinary markers, urinary CTX (U-CTX), N-telopeptide (NTX), pyridinoline (Pyr) and deoxypyridinoline (Dpyr) were measured. Day-to-day physiological variations were different between bone markers. Variability of serum markers was less than that of urinary markers. Moreover, in the comparison of the same molecular marker, CTX, the variability of S-CTX was less than U-CTX. One should consider physiological variation of the marker to evaluate whether the change of the biochemical marker of bone turnover is significant or not.
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PMID:Biological variability of biochemical markers of bone turnover in healthy women. 1248 74

Xenoestrogens, phytoestrogens and synthetic estrogens, are able to bind to estrogen receptors, and to mimic estrogenic activities in a cell and tissue specific manner. For the characterization of environmental estrogens mainly mammary derived and yeast based models have been used. The aim of this study was therefore to assess selected natural and synthetic compounds in an endometrial derived model. We measured the relative estrogenic potency of phytoestrogens (genistein, daidzein, coumestrol, some naringenins), synthetic estrogens (bisphenol A, octylphenol, nonylphenol, o,p'-DDT), mycoestrogen (zearalanone) as well as extracts of Cimicifuga racemosa on alkaline phosphatase (AlkP) activity in the endometrial derived adenocarcinoma cell line Ishikawa. We used a modified multiwell plate in vitro bioassay based on the estrogen-specific and dose-dependent enhancement of AlkP activity in this cell line. Estradiol, which induced AlkP at levels as low as 10(-8)M, was used as positive control. Most of the compounds studied showed a clear dose-dependent estrogenic effect. Compared to the vehicle control (ethanol) all phyto- and mycoestrogens, stimulated the AlkP activity 2-4-fold at a concentration of 10(-6)M. The synthetic chemicals bisphenol A and nonylphenol showed an effect at 10(-6)M, octylphenol at 10(-5)M. Effects of o,p'-DTT could not be measured. ICI 182,780, a pure estrogen receptor antagonist, significantly inhibited these effects. The latter result demonstrated the estrogen receptor dependency of this process. In summary, most of the phytoestrogens and industrial chemicals tested, behaved as estrogen receptor agonists in terms of the stimulation of AlkP activity.
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PMID:Stimulation of alkaline phosphatase activity in Ishikawa cells induced by various phytoestrogens and synthetic estrogens. 1265 Jul 20


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