Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carboxyterminal propeptide of type I procollagen is a biochemical marker of type I collagen synthesis. We evaluated circulating carboxyterminal propetide of type I procollagen levels in patients with terminal renal failure before and after kidney transplantation. Serum carboxyterminal propeptide of type I procollagen, osteocalcin, total alkaline phosphatase, intact parathyrin, creatinine, calcium and phosphate levels were determined in 20 patients, before and 15, 30, 90 and 180 days after surgery. Serum creatinine and intact parathyrin concentrations showed a significant decrease after kidney transplantation. Immunosuppressive treatment consisted of low dose prednisone, cyclosporin and antilymphoblast globulin. In our group, only 5 patients (25%) showed serum carboxyterminal propeptide of type I procollagen levels higher than normal before kidney transplantation. At 15 and 30 days, carboxyterminal propeptide of type I procollagen concentrations showed a decrease, while at 90 and 180 days there was a significant increase above the normal range (p = 0.006; ANOVA). Serum osteocalcin and total alkaline phosphatase levels increased significantly at the same time. We found a significant correlation between carboxyterminal propetide of type I procollagen and osteocalcin at 15 and 30 days after kidney transplantation. We conclude that the significant increase in carboxyterminal propeptide of type I procollagen levels after kidney transplantation reflect an increase in bone turnover. The low doses of steroids employed do not seem to have a significant inhibitory effect on collagen synthesis.
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PMID:Evolution of circulating C-terminal propeptide of type I procollagen in patients with chronic renal failure pre and post renal transplantation. 896 Apr 63

We compared the separate effects of 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analog, 1alpha,25-dihydroxy-16ene,23yne-vitamin D3 (1alpha25(OH)2-16ene,23yne-D3), as well as their interactions with 17-beta estradiol (E2) in our human osteosarcoma SaOS-2 cell models representing two stages of differentiation, the SaOS+DEX and SaOS-DEX cells. SaOS+DEX cells have been previously shown to express higher PTH-stimulated adenylate cyclase (PTH-AC) and basal alkaline phosphatase (ALP) activities compared with SaOS-DEX cells. ALP: In SaOS+DEX cells, 0.1 nmol/L analog, but not 1alpha,25(OH)2D3, increased ALP activity 1.7-fold (p < 0.05). Instead, 1 nmol/L 1alpha,25(OH)2D3 increased ALP 1.4-fold (p < 0.05). In these cells, E2 enhanced 1alpha,25(OH)2D3-stimulated ALP activity (ANOVA, F = 51.22, p <0.0001), while inhibiting the effect of the analog. [3H]-Thymidine uptake: In SaOS+DEX cells, 1alpha,25(OH)2D3 had biphasic effects (ANOVA, F = 13.08, p < 0.0001), which were not altered by E2. In contrast, the analog was stimulatory only with E2 (ANOVA, F = 3.59, p < 0.025). Osteocalcin (OC): 1alpha,25(OH)2D3 and its analog stimulated OC production in SaOS-DEX cells with smaller effects in SaOS+DEX cells. In SaOS-DEX cells, E2 enhanced the effect of 1alpha,25(OH)2D3, but not that of the analog. PTH-AC: In SaOS-DEX cells, 100 nmol/L analog inhibited PTH-AC activities by 50% (p < 0.01), whereas 1alpha,25(OH)2D3 had little effect. In SaOS+DEX cells, both compounds inhibited PTH-AC approximately 35%. E2 inhibited the effect of the analog in SaOS-DEX cells, but enhanced the effects of both compounds in SaOS+DEX cells. These results show that the analog 1alpha,25(OH)2-16ene,23yne-D3 was effective in regulating osteoblastic function; its effects were modulated by E2 and dependent upon the stage of osteoblast differentiation.
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PMID:Effects of 1alpha,25-dihydroxy-16ene, 23yne-vitamin D3 on osteoblastic function in human osteosarcoma SaOS-2 cells: differentiation-stage dependence and modulation by 17-beta estradiol. 896 29

We have studied the effect of different doses of 1 alpha-hydroxycalciferol (1 alpha [OH]D3) on bone mineral density (BMD) of 165 male hemodialysis patients (ages from 24 to 71 years) using dual X-ray absorptiometry (DXA) in a one-year follow-up study. There were no fractures in their lumbar spine participated in the study. 1 alpha (OH)D3 was administered orally at a low dose (0.25 microgram/day, n = 56, Group L) or at a higher dose (0.5 to 1.0 microgram/day, average 0.58 +/- 0.02 microgram/day, n = 65, Group H), and the absolute BMD values and the percent annual changes of BMD were compared with those who took no 1 alpha (OH)D3 (n = 44, Group N). BMD was measured three ways at the start and the end of the study; 1) lumbar spine BMD at anterior-posterior view (AP-BMD), 2) lumbar spine BMD at lateral view (Lat-BMD), and 3) 1/3 distal radius BMD. Plain spinal radiographs indicated no bone fracture before nor during the study. Although there were no detectable changes in the absolute values of BMD during the one-year period, significant differences were observed in the percent annual changes of lumbar spine BMD among the three groups. The annual changes of lumbar spine BMD among the three groups. The annual changes of AP-BMD were -0.4 +/- 0.7%, +0.1 +/- 0.6%, and +2.4 +/- 0.8% in Group N, Group L and Group H, respectively. These changes were statistically significant (p = 0.011 by one-way ANOVA). The positive effect of 1 alpha (OH)D3 on Lat-BMD was also significant (p = 0.028 by one-way ANOVA), while the treatment did not affect the change of BMD at 1/3 distal radius. There was no significant difference among the three groups in the initial or final levels of biochemical parameters including serum calcium, phosphorus, alkaline phosphatase, osteocalcin and parathyroid hormone. These results indicate, in male hemodialysis patients, that oral 1 alpha (OH)D3 treatment is effective in the prevention of lumbar spine BMD loss which is frequently observed in hemodialysis patients.
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PMID:The effect of oral 1 alpha-hydroxycalciferol treatment on bone mineral density in hemodialysis patients. 898 55

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

Biochemical markers of bone metabolism (bone markers) are used increasingly to monitor response to therapy and may be predictors of bone loss and fractures. The relationship between fracture rates, which differ between countries, and the rate of bone turnover has not been examined. Therefore, we explored the geographic variability of bone turnover in a selected, healthy study population of 619 postmenopausal women, ages 40-61, participating in a clinical trial of raloxifene hydrochloride for osteoporosis prevention. The subjects were distributed among 38 investigative sites in 10 countries (9-211 subjects/country) on four continents (North America, n = 277, Europe, n = 168, Australia, n = 125, and Africa, n = 49). Specimens for serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urine type I collagen fragment/urinary creatinine ratio (CTX) were handled in a uniform fashion and assayed in a central laboratory. Mean levels of OC (P < 0.001), BSAP (P = 0. 006), and CTX (P < 0.001) varied significantly by country (ANOVA), with the lowest values typically in German and Spanish subjects and the highest in American and Canadian subjects. The consistent pattern and wide ranges of mean bone marker values (OC 1.6-fold, BSAP 1.7-fold, CTX 3.1-fold) between countries suggest clinically significant differences in bone turnover. Geographic differences in bone markers were not explained by the determined potential confounders of age, years posthysterectomy, total serum cholesterol, and serum follicle stimulating hormone (FSH). We conclude that bone marker values vary substantially by country in this selected study population, suggesting systematic geographic differences in bone metabolism that potentially relate to osteoporotic fracture rates.
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PMID:Geographic differences in bone turnover: data from a multinational study in healthy postmenopausal women. 974 83

A kinetic enzyme immunoassay was developed and validated to quantitate human antibodies to the humanized monoclonal antibody CAMPATH1-1H (C1H) in human serum. The assay was configured using C1H-coated 96-well plates which were blocked with bovine serum albumin, and incubated with dilutions of human serum containing anti-C1H antibody. Antibody was detected using biotinylated C1H followed by streptavidin-conjugated alkaline phosphatase and p-nitrophenyl phosphate. Absorbance data were collected for 10 min, and mOD min-1 data were exported to MultiCalc data analysis software. A 4-parameter logistic-log algorithm was shown to model the data through the range of the standard curve within 15% of nominal values. The overall assay performance coefficient of variation by ANOVA was 9.2%. The lower limit of detection was defined at 160 Units ml-1. The anti-idiotype antibody standard stock solution is stable at 4 degrees C and at -80 degrees C for at least 11 months in buffer. The anti-idiotype antibody controls are stable for at least seven freeze-thaw cycles and at least 6 months in human serum stored at -20 degrees C. A strategy was devised by which to establish the specific antibody potency for any given batch of anti-C1H antibody standard relative to the Reference Standard. This EIA has been used to quantify and characterize anti-C1H antibody in human serum in support of clinical safety and efficacy studies.
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PMID:A kinetic enzyme immunoassay for the quantitation of antibodies to a humanized monoclonal antibody in human serum. 977 6

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

Liposomes, artificial membranous lipid vesicles, have been used as model structures for biological calcification processes. However, there is no definite conclusion that liposomes can be like matrix vesicles for inducing bone calcification and bone-like tissue formation on primary cultured cells. To determine whether liposomes can promote bone cell growth and mineralization by inducing crystal nucleation, liposomes composed of egg phosphatidylcholine, cholesterol, and bovine brain phosphatidylserine were added to 21-day-old Sprague-Dawley fetal rat calvarial cell cultures from day 1. The aims were to observe proliferation and the phenotype of osteoblasts by measuring cell numbers and alkaline phosphatase (ALP) activity and, when added at confluence, to observe calcification. The data were analyzed with two-way ANOVA. During the 16-day culture period, cell numbers were not significantly affected by liposomes (100 mumol/L). However, ALP activity was significantly inhibited by liposomes (p < 0.05) at day 16 and thereafter. Calcified particles were detected by von Kossa's method, and were larger and more abundant (p < 0.05) in the liposomes groups than in the control from days 12-24. This response depended on liposomes dose. These findings suggest that liposomes promote calcification and accelerate the formation of bone-like tissue. Liposomes slightly reduce the expression of the osteoblast phenotype and do not affect cell growth in primary rat osteoblast-enriched cultures.
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PMID:Effect of liposomes on mineralization in rat osteoblast-enriched cultures. 1033 Jul 97

Twenty-five years after the first paper on etidronate in Paget's disease, there are few published papers that address bisphosphonate resistance as a specific clinical phenomenon. We report our data from two studies. Study 1 is a retrospective study of 20 patients with moderate to severe disease who were treated with intravenous (iv) pamidronate (221 +/- 18 mg [SEM]; range 60-360 mg), and after biochemical remission and relapse were retreated with generally larger iv dosage (293 +/- 28 mg; range 180-600 mg). The nadir bone turnover values were similar: plasma alkaline phosphatase (pAP) in 20 patients was 243 +/- 40 IU/l (mean +/- SEM) after the first course, and 267 +/- 44 IU/l after the second (reference range [RR] 35-135 IU/l). Likewise, fasting urinary hydroxyproline excretion (HypE) in 14 of the 20 patients was 4.5 +/- 1.1 micromol/LGF and 4.1 +/- 0.9 micromol/LGF, respectively (RR 0.40-1.92 micromol/LGF). However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 +/- 1.7 months (first) and 5.6 +/- 0.9 months (second) (p < 0.03; Friedman's ANOVA n = 17). A subgroup of 10 patients who were followed for three courses showed a significantly higher pAP nadir in the third course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated with iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly allocated to either oral alendronate 40 mg daily in 3 month units, or iv pamidronate 60 mg every 3 months. Treatment was continued until pAP and fasting urinary deoxypyridinoline/creatinine (Dpy/Cr) ratios (RR 5-27 micromol/mol) were both in the reference range, or a clear plateau in each marker developed. At baseline, there were no significant differences in either marker between the two NILPREV groups and between the two PAMPREV groups. Using log-transformed data, in NILPREV the pAP reductions were significant and similar over the first 6 months. However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p < 0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (pAP p < 0.02; Dpy/Cr p < 0.002). Using two-way ANOVA, the pAP responses to alendronate in NILPREV and PAMPREV were similar and those to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 months or earlier were identical in NILPREV patients: alendronate 87% and pamidronate 87%. However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with the same aminobisphosphonates for two courses show similar nadir values of bone turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendronate/pamidronate comparison, NILPREV and PAMPREV patients showed similar pAP responses to alendronate, but significantly different responses to pamidronate. Thus, patients showing acquired partial resistance to one aminobisphosphonate (usually after two or more previous courses) are still capable of remission after exposure to another compound of the same class.
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PMID:Paget's disease: acquired resistance to one aminobisphosphonate with retained response to another. 1051 Feb 19


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