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 local tissue metabolism is controlled through the complex interaction between systemic and local growth factors. In recent years, an increasing number of autocrine or paracrine growth regulators have been identified in physeal cartilage. While these factors act to alter chondrocytes phenotypically and presumably are important mediators in the process of endochondral ossification, the manner in which they interact with the systemically regulated growth factor insulin-like growth factor-I is unknown. In the present study, the interactive effects of insulin-like growth factor-I with transforming growth factor-beta 1 or basic fibroblast growth factor were examined in short-term monolayer cultures of chick growth plate chondrocytes. [3H]thymidine incorporation was maximally stimulated 11-fold by fibroblast growth factor (10 ng/ml) and 3.5-fold by transforming growth factor-beta 1 following a 24-hour exposure in serum-containing cultures. The effects of transforming growth factor-beta 1 and fibroblast growth factor at both high and low concentrations were enhanced in a dose-dependent manner by insulin-like growth factor-I, with a 40-50% increase in DNA synthesis in the presence of 100 ng/ml of insulin-like growth factor-I. Since insulin-like growth factor-I increased [3H]thymidine incorporation after 48 hours (50% increase) but not after 24 hours of exposure, these observations represent a synergistic interaction. Total DNA in cultures treated for 5 days confirmed the modulating effect of insulin-like growth factor-I with transforming growth factor-beta 1 and fibroblast growth factor. The growth factors were further examined for their effects on markers of chondrocyte differentiation. While all three caused a dose-dependent inhibition of alkaline phosphatase activity, the effects of insulin-like growth factor-I were additive only to those of transforming growth factor-beta 1 and fibroblast growth factor. Similarly, insulin-like growth factor-I did not affect the sulfate incorporation stimulated by fibroblast growth factor or transforming growth factor-beta 1. Insulin-like growth factor-I had no effect on total protein synthesis after 24 hours and, although type-II collagen mRNA levels were stimulated, it had no effect on type-X collagen mRNA, as determined by quantitative in situ hybridization. Finally, insulin-like growth factor-I did not alter the dose-dependent stimulation of noncollagen protein synthesis and the inhibition of collagen synthesis caused by fibroblast growth factor and transforming growth factor-beta 1 in 24-hour cultures. Thus, the data suggest that insulin-like growth factor-I may have a role in augmenting the effects of other growth factors found in cartilage.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of transforming growth factor-beta 1 and fibroblast growth factor on DNA synthesis in growth plate chondrocytes are enhanced by insulin-like growth factor-I. 820 83

Nandrolone decanoate (ND) is an anabolic steroid with a positive effect on bone mass in osteoporotic patients. The mechanism of action, (i.e., reduction of bone resorption and/or stimulation of bone formation), the ultimate effect on mechanical properties, and the most effective dosage are not yet clear. To address these issues, dose-related effects of the long-term effect of ND on serum and bone biochemistry, bone mineral content, and bone mechanical properties in ovariectomized (OVX) rats (12 weeks old at the start of the experiment) were studied for 6 months. The results were compared with those obtained in age-matched, intact, and OVX rats. OVX caused in the femur a significant increase in net periosteal bone formation and net endosteal bone resorption of bone collagen content and torsional strength, and of serum alkaline phosphatase, osteocalcin, and insulin-like growth factor-I (IGF-I) levels, whereas cortical bone density and calcium/creatinine and phosphorus/creatinine in 24-hour urine were significantly reduced. Treatment of OVX rats with 1 mg ND/14 days resulted in a significant increase in periosteal bone formation, femur length, cortical and trabecular bone mineral content and density, torsion stiffness and strength, and bone IGF-I content, and a decrease in serum osteocalcin, urinary calcium/creatinine levels, and bone collagen content compared with OVX controls. The higher ND dosage of 2.5 mg/14 days did not improve the results. ND treatment did not reverse all changes induced by OVS to the level of the intact controls. These results indicate that ND acts as an antiresorptive drug and as a home formation stimulating drug.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Mechanical properties, bone mineral content, and bone composition (collagen, osteocalcin, IGF-I) of the rat femur: influence of ovariectomy and nandrolone decanoate (anabolic steroid) treatment. 827 56

The 1,25-dihydroxyvitamin-D3-(calcitriol)-induced medium osteocalcin and cellular osteocalcin mRNA concentrations are increased in a dose-dependent and time-dependent manner by prior treatment of the human MG-63 osteosarcoma cells with insulin-like growth factor-I (IGF-I). In addition, IGF-I reverses the inhibitory effects of dexamethasone and enhances the effects of retinoic acid on osteocalcin synthesis. The stimulatory effect of IGF-I on osteocalcin synthesis is accompanied by stabilization of osteocalcin mRNA and a decrease of AP-1 binding to the osteocalcin promoter. The binding of the vitamin-D receptor (VDR) to its cognate response element is not affected by IGF-I. In contrast to its effects on osteocalcin synthesis, both baseline and calcitriol-stimulated alkaline phosphatase activities are decreased by IGF-I treatment. Furthermore, IGF-I has mitogenic effects on MG-63 cells. The proliferation of the cells and the levels of c-jun mRNA are greatly increased during IGF-I treatment. Calcitriol reduces or eliminates both these effects. The low concentrations of IGF-I used in this study suggest that IGF-I is an important normal regulator of the synthesis of osteocalcin, a bone calcium-binding protein participating in bone mineralization, by modulating the effects of steroid hormones on its synthesis.
 ...
PMID:Insulin-like growth factor-1 modulates steroid hormone effects on osteocalcin synthesis in human MG-63 osteosarcoma cells. 828 40

Serum bone Gla protein (BGP), a marker of osteoblastic function, serum carboxyterminal cross-linked telopeptide of type I collagen (ICTP), a marker of bone resorption, and serum aminoterminal propeptide of type III procollagen (PIIINP) levels, an index of collagen synthesis, were determined in seven children and eight adults with congenital growth hormone deficiency (GHD). In children with GHD, serum BGP (mean +/- s.e.: 12.9 +/- 0.7 ng/ml), ICTP (8.3 +/- 1.3 ng/ml) and PIINP (3.5 +/- 0.5 ng/ml) levels were significantly lower (P < 0.001) than those recorded in normal children (BGP 18.9 +/- 0.8 ng/ml, ICTP 14.4 +/- 0.5 ng/ml and PIIINP 6.7 +/- 0.7 ng/ml). Total alkaline phosphatase (184.7 +/- 13.4 IU/l) and bone alkaline phosphatase (77.8 +/- 4.1 IU/l) levels were also significantly lower (P < 0.0001) than in controls (338.1 +/- 14.9 IU/l and 181.0 +/- 7.8 IU/l, respectively). Serum BGP, ICTP and PIIINP levels were not significantly correlated with height velocity values. In adults with GHD, mean BGP levels (3.8 +/- 0.3 ng/ml) were significantly lower (P < 0.0001) than those recorded in normals (5.4 +/- 0.1 ng/ml). On the contrary, serum ICTP levels were similar to those found in controls (patients: 4.7 +/- 0.8 ng/ml vs normals: 4.1 +/- 0.3 ng/ml), suggesting the presence of a normal resorption activity associated with a reduced osteoblastic function. This finding was also confirmed by the presence of reduced bone alkaline phosphatase levels (GHD: 44.9 +/- 6.9 IU/I vs controls: 58.3 +/- 2.0 IU/I; P<0.02), while the less specific total alkaline phosphatase levels (119.5 +/- 14.8 IU/I) were similar to those recorded in normal subjects (122.3 +/- 4.0 IU/I). Serum PIIINP levels (3.7 +/- 0.6 ng/ml) were similar to those recorded in normals (3.2 +/- 0.2 ng/ml), suggesting that in adulthood the collagen turnover is not negatively influenced by the chronic GHD. No significant correlations were found between BGP/ICTP/PIIINP and IGF-I levels. In conclusion, our data show that in children with GHD the lack of GH insulin-like growth factor-I (IGF-I) effects on bone and collagen turnover is associated with a significant reduction of bone turnover (low bone formation plus low bone resoRption) and collagen synthesis. On the contrary, adult GHD seems to exert less relevant effects on bone and collagen turnover, probably due to the fact that in adult life further hormones or local factors might partially counteract the negative consequences of chronic GH-IGF-I deficiency.
 ...
PMID:New markers of bone and collagen turnover in children and adults with growth hormone deficiency. 829 Apr 28

The effects of insulin-like growth factor-I (IGF-I) and IGF-II on the human osteoblast cell-line OHS-4 were investigated. Both IGF-I and IGF-II stimulated cell proliferation at nanomolar concentrations and alkaline phosphatase activity was decreased in a dose-dependent manner with either IGF-I or IGF-II. The production of the bone-specific protein osteocalcin was not influenced by either IGF-I or IGF-II. However, they acted synergistically with 1,25-dihydroxy-vitamin D3 at concentrations ranging from 10 to 100 nmol/l. Neither IGF-I nor IGF-II had an effect on either the basal or the parathyroid hormone-stimulated level of adenylate cyclase activity, and likewise they had no effect on phosphodiesterase activity. Binding and cross-linking experiments confirmed the presence of both type-I and type-II IGF receptors on the OHS-4 cells. The present study shows that IGF-I and IGF-II have similar effects on the parameters studied in these osteoblastic cells. They influenced both proliferation and differentiation markers.
 ...
PMID:Comparison of the effects of insulin-like growth factors-I and -II on the human osteosarcoma cell line OHS-4. 842 72

Whether the anabolic effect of insulin-like growth factor-I (IGF-I) in osteoblastic MC3T3-E1 cells is modulated by zinc, an activator of bone formation, was investigated in vitro. After subculture for 3 days, the cells were cultured for 72 h with IGF-I (10(-8) M). The peptide produced a significant increase of protein concentration, deoxyribonucleic acid (DNA) content, and cell number in the cells. These increases were markedly enhanced by the presence of zinc sulfate (10(-5) M), but not zinc-chelating dipeptide (beta-alanyl-L-histidinato zinc; 10(-5) M). Also, the cellular alkaline phosphatase activity was synergistically increased by the presence of both IGF-I and zinc sulfate. Thus, effect was not seen in the presence of both insulin (10(-8) M) and zinc sulfate (10(-5) M). The effect of zinc sulfate to enhance the IGF-I-increased alkaline phosphatase activity and protein concentration in the cells was clearly prevented by the presence of cycloheximide (10(-6) M), staurosporin (10(-8) M), or okadaic acid (10(-7) M) with an effective concentration. However, staurosporin had a partial inhibiting effect on the IGF-I or the IGF-I plus zinc-induced increases in cellular protein, although okadaic acid entirely blocked the IGF-I or the IGF-I plus zinc effect. The present study demonstrates that the anabolic effect of IGF-I in osteoblastic cells is enhanced by zinc ion. The enhancement by zinc may be mediated through the signaling pathway of protein kinase C and protein phosphatase in the cells.
 ...
PMID:Zinc modulation of insulin-like growth factor's effect in osteoblastic MC3T3-E1 cells. 853 89

We evaluated the effects of recombinant insulin-like growth factor-I (IGF-I) and growth hormone (GH) on calciotropic hormones and bone turnover markers in 16 healthy elderly women 71.9 +/- 1.3 years of age (mean +/- SEM). Subjects consumed a fixed diet providing 1000 mg of calcium and 0.9 g/kg of protein for 10 days before starting baseline 24-h urine and blood collections. Specimens were collected for 6 consecutive days before initiating subcutaneous injections of GH (25 micrograms/kg/day, n = 5) and IGF-I at 60 micrograms/kg b.i.d. (high-dose, n = 5) or at 15 micrograms/kg b.i.d. (low-dose, n = 6) for 28 days. Resorption markers included urine hydroxyproline (OHP), total pyridinolines (PYD), and N-telopeptide; formation markers include osteocalcin, skeletal alkaline phosphatase (sALP), and type I procollagen carboxy-terminal extension peptide (CICP). For each subject, baseline daily turnover markers varied substantially (DV = 16-22%). With GH and high-dose IGF-I, resorption and formation markers increased progressively to maximum levels at day 21. For GH, the increase in day 21 PYD, N-telopeptide, osteocalcin, and CICP was 143, 111, 53, and 81%, respectively (p < 0.96-0.02). For high-dose IGF-I, these increases were 108, 81, 77, and 111% (p < 0.02-0.002). However, with low-dose IGF-I no change was observed in resorption markers while osteocalcin and CICP increased progressively (day 21, % increases = 88 +/- 51, 36 +/- 14). Twenty-four hour urine collections during the last days of baseline and of study drug were taken as six 4 h aliquots. When deoxyPYD was measured on these samples in the low-dose IGF-I group, a significant increase was observed only on the 0800-1200 h aliquot. Serum phosphorus concentrations increased with GH (21.2 +/- 3.3%) and high-dose IGF-I (8.8 +/- 3.6%) by day 21 but actually decreased by day 28 (-9.7 +/- 2.7, p < 0.02) with low-dose IGF-I. Urinary phosphorus excretion decreased with high-dose IGF-I only. Twenty-four hour calcium excretion increased with all treatments. These results indicate that both GH and high-dose IGF-I activate remodeling osteons. By contrast, low-dose IGF-I may directly increase osteoblastic function with only a minimal increase in bone resorption and may therefore provide a useful means to increase bone mass. The results also suggest some of the GH action on renal phosphorus handling represents a direct action of GH on the nephron which does not involve the intermediacy of IGF-I. Finally, even under controlled conditions bone turnover markers exhibit substantial daily variation so that a very large treatment effect will be required for these markers to have clinical utility.
 ...
PMID:Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. 861 64

Bone metabolism was assessed in 56 Ile de Francex(RomanovxLimousine) fetal lambs killed between Day 80 and Day 145 of gestation. In each fetus, the length, width and weight, as well as the calcium and phosphorus content of the left diaphyseal metacarpal bone were measured. Plasma alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities, bone ALP (B-ALP), osteocalcin (OC) and insulin-like growth factor-I (IGF-I) were assayed in these fetuses and in six newborn lambs from birth until one month after birth. Fetal growth is characterized by an increase in bodyweight, bone size and bone mineral content from Day 80 to Day 132 of gestation. These parameters did not significantly vary until birth. Plasma concentrations of IGF-1, OC and B-ALP increased from Day 80 to Day 132. Between Day 132 and birth, plasma IGF-I and B-ALP concentrations did not significantly vary, whereas plasma OC concentration decreased, confirming the usefulness of OC as a marker of osteoblastic activity and bone formation in the ovine species. The increase in plasma IGF-I, B-ALP and OC concentrations observed during the first two weeks of postnatal life indicate an intense skeletal growth in these animals, which was confirmed by the bodyweight growth curve.
 ...
PMID:Metacarpal growth and systemic markers of bone metabolism in the ovine fetus. 872 68

The expression of insulin-like growth factor-I (IGF-I), interleukin-6 (IL-6), and transforming growth factor-beta 1 (TGF-beta 1) mRNA in rat femurs was examined following marrow ablation. Northern blot analysis showed multiple transcripts of IGF-I, a major transcript of 1.3 kb and a minor one of 2.4 kb for IL-6 and a single band of 2.5 kb for TGF-beta 1, respectively. Examination of the temporal activation pattern showed IGF-I expression peaked at day 3 (150% over the basal level) after injury and preceded the maximal expression of procollagen alpha 1(I), osteopontin, alkaline phosphatase, and osteocalcin mRNAs. This suggests that IGF-I is involved mainly in osteoblast development and bone formation. In contrast, IL-6 expression was elevated between days 3 and 9 (45-60% over the basal level). The sustained elevation of IL-6 expression at day 9 is consistent with the role for this cytokine in the development of osteoclasts and bone resorption. The expression of TGF-beta 1 was not altered up to day 9 after marrow ablation. While the temporal expression patterns of IGF-I and IL-6 mRNA did not differ between adult and old rats, the maximal level of IGF-I mRNA at day 3 was 72% higher in adult as compared to old bones. In contrast, the peak level of IL-6 mRNA at days 6-9 was 45% higher in old as compared to adult bones. Although the level of TGF-beta 1 mRNA did not change following marrow ablation, levels of TGF-beta 1 were consistently higher in old rats. Our results suggest that the impaired bone formation and elevated bone resorption in aged animals may be due in part to the reduced expression of IGF-I and an overexpression of IL-6 in old bone.
 ...
PMID:Effect of age on the expression of insulin-like growth factor-I, interleukin-6, and transforming growth factor-beta mRNAs in rat femurs following marrow ablation. 873 6

We evaluated the radiological, biochemical and growth hormone (GH)/insulin-like growth factor-I (IGF-I) changes in 10 children with severe protein-energy malnutrition (PEM) who had rachitic manifestations (group 1), 10 children with severe PEM without clinical signs of rickets (group 2), and 10 children with normal body weight-for-length and -age, suffering from vitamin-D-deficiency with signs of florid rickets (group 3) and 10 normal age-matched children (group 4). Serum calcium (Ca2+), phosphorus (PO4), and albumin concentrations were markedly decreased in the two groups with PEM. Malnourished children with rickets had significantly higher serum alkaline phosphatase (ALP) concentrations compared to the malnourished group without rachitic manifestations. Radiological evaluation of the two groups who had rachitic manifestations revealed demineralization of long bones, thinning of the bony cortex, increased formation of osteoid tissue, and metaphyseal changes including cupping, fraying, and flaring. The incidence of these radiological findings did not differ among the well-nourished and the malnourished groups with clinical signs of rickets. However, the incidence of fracture of the shaft was higher (40 per cent) in the malnourished group compared to the well-nourished group (10 per cent) with rickets. In the malnourished group without clinical evidence of rickets, demineralization and cortical thinning was detected in 40 per cent without significant metaphyseal changes. Basal concentrations of GH and peak GH response to clonidine were significantly elevated and IGF-I concentrations were significantly depressed in the malnourished groups v. the other two groups. There were no significant differences in the fasting and the clonidine provoked GH levels or IGF-I concentrations between the rachitic children (group 3) and the normal children. These data suggest that in rachitic children there is not a major role for circulating GH (and by implication IGF-I) on bone mineralization. However, during malnutrition decreased IGF-I production can slow or stop epiphyseal growth and might contribute to the demineralization of the cortex of long bones.
 ...
PMID:Radiological, biochemical, and hormonal changes in malnourished children with rachitic manifestations. 882 Jun 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>