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)

Our previous work has shown that, in the normal circulation, insulin-like growth factor-binding protein-1 (IGFBP-1) is present as a single highly phosphorylated species. In this study, we have purified this previously uncharacterized isoform of IGFBP-1 to determine its ligand-binding affinity and the potential significance of highly phosphorylated IGFBP-I. Immunoaffinity chromatography was used to isolate IGFBP-1 from normal human plasma and from human hepatoma (Hep G2) cell medium as an alternative source of the IGFBP-1 phosphoform in the circulation. The affinity of this highly phosphorylated IGFBP-1 was compared with that of nonphosphorylated IGFBP-1 and recombinant human (rh) IGFBP-3 by equilibrium binding to IGF-II and IGF-II. Anion exchange (IEX) HPLC, nondenaturing electrophoresis, alkaline phosphatase treatment, and ligand-binding studies indicated that the highly phosphorylated IGFBP-1 from HepG2 cells was comparable with IGFBP-1 from plasma. In binding to IGF-I, the plasma phosphoform of IGFBP-1 was found to have a higher affinity (2.3 +/- 1.1 x 10(10) M-1) than nonphosphorylated IGFBP-1 (2.5 +/- 1.7 x 10(9) M-1, P < 0.002). However, when binding to IGF-II, phosphorylation had no affect on the affinity of IGFBP-1 (3.6 +/- 2 x 10(9) M-1 vs. 1.8 +/- 3 x 10(9) M-1, P not significant). Therefore, in the circulation, IGF-I has a considerably higher affinity than IGF-II for IGFBP-1 (P < 0.02). The affinity of phosphorylated IGFBP-1 from plasma (2.3 +/- 1.1 x 10(10) M-1) also was significantly higher than the affinity of IGFBP-3 for IGF-I (5.6 +/- 4.2 x 10(9) M-1, P < 0.005). These data suggest that the highly phosphorylated IGFBP-1 in the normal circulation will preferentially bind IGF-I rather than IGF-II, whereas in pregnancy, the affinity of IGFBP-1 for IGF-I will be reduced because of the appearance of non- and lesser-phosphorylated forms. This lends support to the theory that changes in IGFBP-1 phosphorylation may influence the modulatory effects of IGFBP-1 on IGF bioavailability.
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PMID:Purification and characterization of the insulin-like growth factor-binding protein-1 phosphoform found in normal plasma. 904 19

Insulin-like growth factors, which are important local factors in bone, are associated with specific binding proteins (IGFBPs). In this study, the relationship between IGFBPs and cell differentiation of MC3T3-E1 cells (E1 cells), a clonal osteoblast-like mouse calvarial cell line, was investigated. IGFBP-3 had no effect on alkaline phosphatase (ALP) activity of E1 cells, but in the presence of IGF-II at an ineffective concentration stimulated ALP activity. ALP activity of E1 cells cultured in alpha-MEM supplemented with 10% fetal calf serum (FCS) gradually increased after confluency, which demonstrated that E1 cells differentiate. In this experiment, 39 kd IGFBP-3 of FCS origin was decreased in the conditioned medium after 48 hours of culture of the cells obtained on day 0 after confluency, but not of those obtained on day 21, which suggests that the use of IGFBP-3 of FCS origin is diminished related with cell differentiation and E1 cells secrete themselves. E1 cells secreted three IGFBP, Mr 23, 26, and 31kd. Secretion of 31kd IGFBP gradually increased, and this increase correlated with ALP activity of E1 cells. These findings suggest that secretion of 31kd IGFBP is related with osteogenic differentiation of E1 cells.
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PMID:[The relationship between insulin-like growth factor-binding proteins and cell differentiation of osteoblastic clone MC3T3-E1 cells]. 908 65

The objectives of this study were to 1) study the GH-insulin-like growth factor (IGF) axis in adult untreated Turner's syndrome compared to that in age-matched controls; 2) examine the effects of sex hormone substitution on this axis, 3) study the effects of route of administration of 17 beta-estradiol on the measured variables, and 4) examine the effects of sex steroids on hepatic function in Turner patients. Twenty-seven patients with Turner's syndrome were evaluated before and during sex hormone replacement, and an age-matched control group (n = 24) was evaluated once. Main outcome variables were GH and other measures of the GH-IGF axis, body composition, maximal oxygen uptake, sex hormone-binding globulin, and hepatic enzymes and proteins. The integrated 24-h GH concentration (IC-GH; micrograms per L/24 h) was reduced in women with Turner's syndrome (T) compared to controls [C; mean +/- SD, 18.3 +/- 12.0 (T) vs. 37.2 +/- 29.7 (C); P = 0.007]. However, multiple regression revealed that fat-free mass (FFM) and maximal oxygen uptake were significant explanatory variables (joint r = 0.77; P < 0.0005), accounting for 60% of the variance in the 24-h IC-GH. This association was also present in controls. After adjustment for these two variables, any difference in GH concentration between Turner patients and controls disappeared. Serum IGF-I and IGF-II were identical in Turner patients and controls despite the difference in 24-h IC-GH. The level of GH-binding protein (GHBP; nanomoles per L) was higher in Turner women [1.87 +/- 0.72 (T) vs. 1.22 +/- 0.33 (C); P = 0.0005]; after adjustment for FFM, the difference in GHBP levels disappeared between Turner patients and controls. During sex hormone treatment a significant increase was seen in the 24-h IC-GH (P = 0.02), FFM (percentage of weight; P < 0.0005) and maximal oxygen uptake (milliliters of O2 per kg/min; P = 0.02). Serum IGF-I was unchanged, whereas serum IGF-II (micrograms per L) decreased significantly [Turner, basal (TB), vs. Turner, treatment (TT), 860 +/- 135 vs. 823 +/- 150; P = 0.04]. Alanine aminotransferase (units per L), gamma-glutamyl transferase (units per L), and alkaline phosphatase (units per L) were significantly elevated during the basal study period, and all decreased during treatment [alanine amino-transferase, 55 +/- 55 (TB) vs. 30 +/- 20 (TT; P = 0.006); gamma-glutamyl transferase, 92 +/- 98 (TB) vs. 43 +/- 65 (TT; P = 0.003); alkaline phosphatase, 211 +/- 113 (TB) vs. 175 +/- 54 (TT); P = 0.06]. The route of administration of 17 beta-estradiol did not affect its actions. In conclusion, we found the GH-IGF axis in Turner's syndrome to be normal, with body composition and physical fitness exerting the same modifying effects on this axis as seen in the normal population. Sex hormone replacement in Turner's syndrome is associated with normalizing effects on the GH-IGF axis, body composition, physical fitness, and hepatic function. The lowering of hepatic enzymes is a surprising and hitherto undiscovered action of sex steroids. Finally, the route of administration of 17 beta-estradiol is of minor importance in Turner's syndrome.
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PMID:Body composition and physical fitness are major determinants of the growth hormone-insulin-like growth factor axis aberrations in adult Turner's syndrome, with important modulations by treatment with 17 beta-estradiol. 925 36

Previous studies have shown that osteogenic protein-1 (OP-1; also known as BMP-7) alters the steady state levels of messenger RNA (mRNA) encoding insulin-like growth factor I (IGF-I), IGF-II, and IGF-binding proteins (IGFBPs) in primary cultures of fetal rat calvaria (FRC) cells. In the present study, the effects of exogenous IGF-I on bone cell differentiation and mineralized bone nodule formation induced by OP-1 were examined. Exogenous IGF-I synergistically and dose dependently enhanced OP-1 action in stimulating [3H]thymidine incorporation, alkaline phosphatase activity, PTH-dependent cAMP level, and bone nodule formation. Maximal synergism between OP-1 and IGF-I was observed when both factors were added simultaneously. Synergism was not observed when FRC cells were pretreated with IGF-I for 24 h, followed by OP-1 treatment. These findings suggest that IGF-I acted on OP-1-sensitized FRC cells. To examine the mechanism(s) by which this sensitization may occur, levels of mRNA encoding OP-1 receptor, IGF-I receptor, and IGFBPs were measured. The mRNA levels of both type I and II OP-1 receptors were elevated by OP-1, but were not changed further by combined OP-1 and IGF-I treatment. IGF-I receptor gene expression was not changed by OP-1, IGF-I, or a combination of both factors. OP-1 alone or together with IGF-I increased the steady state IGFBP-3 mRNA level and reduced the steady state mRNA levels of IGFBP-4, -5, and -6. IGF-I alone did not change the steady state mRNA levels of IGFBP-3, -4, and -6, but elevated that of IGFBP-5. Des(1-3)-IGF-I, which has a lower affinity for IGFBPs, was more effective than the full-length IGF-I in enhancing the OP-1-induced alkaline phosphatase activity. Exogenous IGFBP-5 inhibited the OP-1-induced alkaline phosphatase activity and reduced the synergistic stimulatory effect of IGF-I and OP-1. These findings strongly suggest that the OP-1-induced down-regulation of IGFBPs, especially that of IGFBP-5, is an important mechanism by which OP-1 and IGF-I synergize to stimulate FRC cell differentiation.
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PMID:Osteogenic protein-1 and insulin-like growth factor I synergistically stimulate rat osteoblastic cell differentiation and proliferation. 932 28

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

The mechanisms which regulate cell turnover in the intestinal epithelium are incompletely understood. The present study was performed to characterize the role of autocrine IGF system components in intestine epithelial cell proliferation and differentiation comparing rapidly growing crypt cells (IEC-6) with differentiating enterocytes (CaCo-2). The autocrine release of IGF-I, IGF-II and IGFBP-1 through -3 was determined by specific RIAs and western ligand blotting. In addition, binding and growth-promoting activity of insulin, IGF-I and IGF-II was investigated. Enterocytic differentiation was assessed by measuring the brush-border enzymes alkaline phosphatase and sucrase. During IEC-6 growth, the autocrine release of IGF-I and -II increased, whereas IGFBP-2 levels decreased. Specific receptors for IGF-I and IGF-II but not insulin could be detected. IGF-I was 100-fold more potent than insulin to stimulate IEC-6 cell proliferation. In contrast, CaCo-2 cells revealed higher binding of insulin than IGF-I/-II and no release of IGF-I. At switch from CaCo-2 cell proliferation to differentiation a marked increase in the secretion of IGF-II (10-fold), IGFBP-1 (2.5-fold), IGFBP-2 (3-fold), and IGFBP-3 (6-fold) was measured. Our data indicate that IGF system components differentially modulate enterocytic cell proliferation and differentiation.
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PMID:Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components. 1022 88

Insulin, insulin-like growth factors (IGF) I and II are considered to play an important part in the growth and differentiation of dental pulp cells. The present study examined the effects of these factors on pulp cells in serum-free culture conditions. The DNA content and alkaline phosphatase (ALPase) activity of dog pulp cells increased when they were cultured in a serum-free medium supplemented with transferrin, yolk lipoprotein and basic fibrobrast growth factor (TYF medium). The pulp cells produced type I collagen but not type III, suggesting that they might proliferate and differentiate into odontoblast-like cells in a serum-free culture. Both IGF-I and IGF-II enhanced the ALPase activity of pulp cells cultured in TYF medium to an equivalent level, but a higher concentration of IGF-II was necessary to produce a similar effect on DNA synthesis to that of IGF-I. Insulin dose-dependently enhanced DNA synthesis and increased ALPase activity, but its effects were weaker than those of the IGFs. These findings suggest that IGF-I might have a primary role in the growth and differentiation of pulp cells.
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PMID:Stimulation of proliferation and differentiation of dog dental pulp cells in serum-free culture medium by insulin-like growth factor. 1034 63

This study used a cross-sectional design to investigate relationships among serum insulin-like growth factor (IGF) parameters (total serum IGF-I, IGF-II, and IGF-binding protein-3), serum estradiol, and bone mineral density (BMD) stratified for potential confounders, and a longitudinal design to investigate the effects of hormonal replacement therapy (HRT) on IGFs and BMD. Five hundred and ninety-five perimenopausal women (median age, 50.0 yr; range, 45-56 yr) participating in the Danish Osteoporosis Prevention Study were investigated in a cross-sectional study, and a randomly selected subgroup of 110 was followed after 5 yr in a longitudinal study for changes in serum IGFs and BMD of lumbar spine, femoral neck, and ultradistal forearm during (n = 46) or without HRT (n = 64). In the cross-sectional study, serum IGF-I correlated positively to distal forearm BMD and spine BMD, but not to femoral neck BMD, after stratification for age, body mass index, and other variables. In the follow-up study, HRT decreased IGF-I and IGF-II, but did not influence the age-related decline in IGF-binding protein-3 significantly. Serum alkaline phosphatase and urinary hydroxyproline/creatinine ratio both decreased during HRT, whereas BMD increased compared to control values. After adjustment for age, body mass index, treatment, and other factors, IGF-I correlated positively to changes in forearm and femoral neck BMD, but not to changes in spine BMD. We conclude that serum IGF-I was positively associated to bone mineral density. Oral HRT decreases IGF-I and IGF-II.
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PMID:Effect of sex hormone replacement on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal women participating in the Danish Osteoporosis Prevention Study. 1040 91

Insulin-like growth factors (IGFs) are important regulators of the activity of mature osteoblasts, but their effects on osteoprogenitor cells in human bone marrow stroma are unclear. In this study, we assessed the effects of IGFs on a conditionally immortalized human marrow stromal cell line, hMS(3-4), which has the ability to differentiate to either mature osteoblasts or adipocytes. hMS(3-4) cells expressed functional receptors for IGFs as well as specific IGF-binding proteins (IGFBP-3, -4, -5, and -6). IGF treatment of hMS(3-4) cells did not alter IGFBP expression, but resulted in distinct posttranslational modifications of secreted IGFBP-3 and IGFBP-4 proteins. IGF-I, IGF-II, and their receptor-activating analogs significantly increased by 2-fold the proliferation rate of the hMS(3-4) cells, but had a more complex effect on hMS(3-4) cell differentiation. Treatment with IGFs did not affect gene expression of Cbfa1 or peroxisome proliferator-activated receptor gamma2 (transcription factors involved in commitment to osteoblast and adipocyte pathways, respectively), alkaline phosphatase, type I collagen, and osteocalcin (markers of the osteoblast lineage), or lipoprotein lipase and adipsin (markers of the adipocyte lineage) and did not change alkaline phosphatase activity or type I collagen and osteocalcin protein relative to total protein production. In contrast, IGFs significantly increased type I collagen expression in differentiated hMS(3-4) cells as well as mature osteoblasts and promoted lipid accumulation in differentiated adipocytes. In summary, hMS(3-4) cells express essential components of the IGF system and respond to IGF treatment with increased proliferation. There was no evidence for IGFs directly modulating the commitment of hMS(3-4) cells to either osteoblast or adipocyte pathways, and their effects on differentiation within these lineages were dependent on the stage of cell maturation.
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PMID:Response of bipotential human marrow stromal cells to insulin-like growth factors: effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes. 1053 29

Both a decrease in bone formation and an increase in bone resorption have been implicated in the pathogenesis of age-related (type II) femoral neck osteoporosis. While the increase in the bone resorption rate has been shown to be partially related to secondary hyperparathyroidism, the mechanisms underlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation deficit associated with type II osteoporosis might be due to secondary hyperparathyroidism and/or to a deficiency of the insulin-like growth factor (IGF) system. Circulating concentrations of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D3), and intact parathyroid hormone (PTH) were measured in 50 elderly women after sustaining a hip fracture and in 50 healthy age-matched controls. In addition, serum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-terminal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP-4 serum levels in the two groups studied, while mean levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, 25(OH)D3, and markers of bone formation were significantly lower (p < 0.006) in patients as compared with healthy subjects. Serum PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of serum OC (R2 = 19%, p < 0.001) and BMD of femoral neck (R2 = 49%, p < 0.0001), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D3 and PTH, however, were statistically unrelated to OC. To address further the potential impact of trauma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in serum level of any of the IGF system components between the two groups. Although limited by its cross-sectional design, the present study suggests that, in addition to bone resorption resulting from secondary hyperparathyroidism, impaired bone formation associated with deficiency of the IGF system might predispose elderly women to fragility fracture of the proximal femur.
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PMID:Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. 1062 75


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