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 recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 microg/kg daily, increasing after 3 months to 80 microg/kg daily. Body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman's minimal model, was substantially reduced at baseline at 1.45 x 10-4 min-1 (microU/mL) [normal value, 5.1 x 10-4 min 1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 microg/kg x day, Si = 2.06 x 10-4 min-l; rhIGF-I dose: 80 microg/kg x day, Si = 4.39 x 10-4 min-1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (-4.88 SD); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4-9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15-41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 microg/kg.day of rhIGF-I. In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.
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PMID:Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion. 1077 Jan 74

Primary disturbances in mineral metabolism and deficiencies in insulin and insulin-like growth factor-I (IGF-I) have been implicated in the pathogenesis of diabetic osteopenia. This prompted us to investigate whether normal bone minerals and bone morphology are preserved after pancreas transplantation. To this end, 8 inbred rats (transplants) were compared with 9 sham-operated rats (controls) 20 months after orthotopic pancreas transplantation. While basal levels of insulin remained unaffected by transplantation, an oral glucose load elicited hyperinsulinemia (integrated incremental response: mean +/- SEM, 62+/-8 nmol l(-1) 60 min in transplants vs. 32+/-6 nmol l(-1) 60 min in controls; p<0.01) in the presence of normal glucose levels. Fecal and urinary excretion and fractional intestinal absorption of calcium, magnesium and phosphorus, net calcium absorption and the respective serum mineral levels were unchanged after transplantation, as were those of the calciotropic hormones. Serum osteocalcin and bone alkaline phosphatase remained unaffected, and urinary excretion of pyridinium and deoxypyridinium were unchanged. Fasting plasma IGF-I concentration was significantly decreased in transplants (930+/-42 ng ml(-1)) vs. control rats (1074+/-49 ng ml(-1); p < 0.05). Despite similar physical and chemical properties of bone in both groups, histomorphometry revealed slight osteopenia in transplant rats, as reflected by a 38% reduction in the cancellous bone area of the proximal tibial metaphysis. Plasma IGF-I levels were significantly correlated with bone mineral apposition rate (r=0.70, p<0.02), osteoblast perimeter (r=0.60, p<0.05) and osteoid perimeter (r=0.60, p<0.05). In conclusion, pancreas transplantation preserves physical and chemical properties of bone, but bone metabolism is not completely normal after transplantation, as evidenced by decreased cancellous bone. This might have resulted from the insulin resistance associated with the lowering of the plasma IGF-I level, which was correlated with the mineral apposition rate.
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PMID:High insulin and low IGF-I plasma levels following pancreas transplantation in rats. Implications for bone and mineral metabolism. 1088 89

Soy isoflavones are hypothesized to exert hormonal effects in women and thus may play a role in bone metabolism throughout life. In 2 randomized, cross-over studies, 14 pre- and 17 postmenopausal women were given 3 soy protein isolates containing different amounts of isoflavones [control, 0.13; low isoflavone (low-iso), 1.00; and high-iso, 2.01 mg/kg body wt/day, averaging 8, 65, and 130 mg/day, respectively], for over 3 months each. Food records, blood samples, and 24-h urine collections were obtained throughout the studies. The endpoints evaluated included plasma or serum concentrations of bone-specific alkaline phosphatase, osteocalcin, insulin-like growth factor-I (IGFI), IGF binding protein-3 (IGFBP3), and urine concentrations of deoxypyridinoline cross-links and carboxy-terminal telopeptide of type I collagen. In premenopausal women, IGFI and IGFBP3 concentrations were increased by the low-iso diet, and deoxypyridinoline cross-links was increased by both the low- and high-iso diets during certain phases of the menstrual cycle. In postmenopausal women, bone-specific alkaline phosphatase was decreased by both the low- and high-iso diets, and there were trends toward decreased osteocalcin, IGFI, and IGFBP3 concentrations with increasing isoflavone consumption. Although soy isoflavones do affect markers of bone turnover, the changes observed were of small magnitude and not likely to be clinically relevant. These data do not support the hypothesis that dietary isoflavones per se exert beneficial effects on bone turnover in women.
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PMID:Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. 1099 83

Although there is clinical evidence showing that combined therapy with parathyroid hormone (PTH) and estrogen is additively effective in increasing the bone mass of patients with osteoporosis, the mechanism of the interaction between these hormones remains unclear. The present study was performed to determine whether estrogen would affect osteoblast proliferation and function modulated by PTH in human osteoblastic SaOS-2 cells. Human PTH-(1-34) significantly inhibited [(3)H]thymidine (TdR) incorporation, which was attenuated by 24 h pretreatment with 10(-10) to 10(-7) M 17 beta-estradiol (17 beta-E(2)) in a concentration-dependent manner. PTH significantly stimulated alkaline phosphatase (ALP) activity, collagen synthesis and type-1 procollagen mRNA expression after pretreatment with 17 beta-E(2 )in these cells. Tamoxifen, an anti-estrogen, antagonized these 17 beta-E(2)-induced effects. Pretreatment with insulin-like growth factor-I (IGF-I) mimicked estrogen action, and coincubation of 3 microg/ml anti-IGF-I antibody antagonized the effects of 17 beta-E(2 )as well as those of IGF-I. In the presence of 17 beta-E(2 )pretreatment, PTH strongly stimulated IGF-binding protein (IGFBP)-5 mRNA expression in these cells, and recombinant IGFBP-5 increased type-1 procollagen mRNA expression and ALP activity. In conclusion, estrogen attenuates PTH-induced inhibition of osteoblast proliferation and PTH stimulates osteoblast function in the presence of estrogen pretreatment. IGF-I and/or IGFBP-5 seemed to be involved in the estrogen-induced modulation of PTH action on osteoblast proliferation and function.
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PMID:Estrogen modulates osteoblast proliferation and function regulated by parathyroid hormone in osteoblastic SaOS-2 cells: role of insulin-like growth factor (IGF)-I and IGF-binding protein-5. 1105 45

A new mouse model of stage-specific bone growth failure and fracture has been recovered as an autosomal recessive mutation, designated spontaneous fracture (sfx). The sfx/sfx mice are phenotypically normal until shortly after weaning, when reduced mobility and impaired somatic growth are first noted. By 6 weeks of age, body, spleen, and thymus weights, as well as hematocrits and serum calcium, inorganic phosphate, total alkaline phosphatase, insulin-like growth factor-I, and osteocalcin levels are decreased. The sfx/sfx mice also show reduced femoral cortical density and diaphyseal circumference, as well as a paucity of mature osteoblasts on bone surfaces. Histological analyses of the femur and tibia in the mutants show subtle reduction of chondrocyte numbers in epiphyseal-plate columns, reduction of matrix, and near absence of osteoid below the differentiated chondrocytes. Trabeculae in proximal tibiae, iliacs, and vertebral bodies are sparse and thin. Cortical bone thickness of mutants is markedly thinned in all sites examined. By 7-8 weeks, radiographic films routinely show spontaneous impact fractures of the distal femur accompanied by callus formation, whereas complete fractures are less commonly observed. Volumetric bone mineral density (BMD) of mutant femurs is similar to +/? littermates in the center of the femoral diaphysis, but BMD declines as either end of the femoral diaphysis is approached. We have mapped the gene responsible for this phenotype to central Chromosome 14. Reduced bone mass, impaired bone formation, abnormalities of bone architecture, and a disposition to spontaneous fracture identify sfx/sfx mice as a useful model for understanding the mechanisms responsible for peripubertal bone formation.
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PMID:Spontaneous fracture (sfx): a mouse genetic model of defective peripubertal bone formation. 1106 47

There are studies concerning the association among endogenous sex steroids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and bone mineral density (BMD) in both men and women. However, little is known concerning the association of these parameters with markers of bone turnover in healthy elderly men. We studied the association of BMD (dual energy X-ray absorptiometry of spine, hip and forearm) and markers of bone turnover (bone-specific alkaline phosphatase, serum C-terminal propeptide of type I collagen, and serum osteocalcin reflecting formation, urine deoxypyridinoline and calcium excretion in relation to creatinine excretion reflecting resorption) with endogenous sex steroids, GH and IGF-I in 14 elderly normal men (age range 60-79 years). There was a negative correlation between age and dehydroepiandrosterone sulphate (DHEAS) (r=-0.60, p=0.022) and a positive correlation between GH and IGF-I (r=0.53, p=0.048). Serum estradiol concentrations correlated with BMD at distal 1/3 radius (r=0.41, p=0.1) and mid-radius (r=0.47, p=0.08), and negatively correlated with age (r=-0.45, p=0.09). There was no correlation of estradiol with bone turnover markers, testosterone, free testosterone, DHEAS, GH and IGF-I. Serum GH and IGF-I levels showed no correlation with BMD (all sites) and bone turnover markers. Serum total testosterone concentrations positively correlated with BMD at distal 1/3 radius (r=0.47, p=0.09), femoral neck (r=0.56, p=0.037) and Ward's triangle (r=0.49, p=0.07). These data suggest that serum estradiol and testosterone levels are associated with BMD in elderly men, possibly indicating their contribution to skeletal maintenance in old age. However, correlations of IGF-I, GH and DHEAS with BMD and bone turnover markers are lacking in the group studied.
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PMID:Endogenous sex steroid, GH and IGF-I levels in normal elderly men: relationships with bone mineral density and markers of bone turnover. 1143 64

Metabolic bone loss is the most common complication of chronic liver disease. However, there is little information available about bone loss in rats with a ligated bile duct, a biliary-type of experimental cirrhosis model. Therefore, in this study, the effect of bile duct ligation (BDL) on bone mineral density (BMD) and plasma insulin-like growth factor-I (IGF-I) levels was examined in rats. Two weeks after BDL operation, the rats with a ligated bile duct showed a pronounced and significant decrease in both trabecular and cortical BMD of the femur. In these rats, decreases in food intake and plasma IGF-I levels plus elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin were also observed. When the effect of dietary restriction (30% or 50%) over 2 weeks was then investigated in normal rats, 50% food restriction resulted in a significant decrease in femoral trabecular bone density although BMD was unchanged by 30% dietary restriction. The plasma levels of IGF-I were also decreased in food-restricted rats. Thus, the decrease in femoral bone density in 50% food-restricted rats was less potent compared with BDL rats; nevertheless, the decrease in plasma levels of IGF-I was almost equally potent in both BDL and food-restricted rats. Overall, this study showed that BDL operation resulted in a pronounced bone loss in rats, but also that this bone loss might not be merely due to the decreases in food intake and plasma IGF-I levels. These results suggest that BDL in rats is a useful experimental cirrhosis model for evaluating the bone loss associated with chronic liver disease.
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PMID:Induction of bone loss by bile duct ligation in rats. 1169 18

Insulin-like growth factor-I (IGF-I) is potent stimulator of proliferation and differentiation of osteoblasts, the biosynthesis of collagen type-I and noncollagenous proteins and alkaline phosphatase activity. The role of IGF-I in bone repair has not as yet been clearly defined. The aim of the present study was the quantitative analysis of IGF-I in the serum and tissue in four phases of fractured jaws healing in rat models. IGF-I concentrations in the serum and bone extracts were determined by RIA. In respect to the control group (K) the significant increase of IGF-I occurred in the serum in phase I (211 +/- 68 ng/ml, K-153 +/- 50 ng/ml) (p < 0.05). At the tissue levels a statistically significant increase in IGF-I was confirmed in phase II (262 +/- 60 ng/g, K-182 +/- 56 ng/g) (p < 0.05). The present results demonstrate that in rat models with fractured jaws in the first two phases of healing elevated levels of IGF-I in the serum and bone tissue were observed which indicate the significant role of this polypeptide in the early healing stages.
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PMID:Insulin-like growth factor-I (IGF-I) in serum and bone tissue during rat mandible fracture healing. 1178 May 72

Menopause drastically increases the risk of osteoporosis. Aside from drug therapy, lifestyle and nutritional factors play an important role in the maintenance of skeletal health. Our recent findings suggest that dried plums, a rich source of phenolic and flavonoid compounds, are highly effective in modulating bone mass in an ovarian hormone-deficient rat model of osteoporosis. The objective of this study was to examine whether the addition of dried plums to the diets of postmenopausal women positively influences markers of bone turnover. Fifty-eight postmenopausal women not on hormone replacement therapy (HRT) were randomly assigned to consume either 100 g dried plums or 75 g dried apples daily for 3 months. Both dried fruit regimens provided similar amount of calories, fat, carbohydrate, and fiber. Serum and urinary biochemical markers of bone status were assessed before and after treatment. In comparison with corresponding baseline values, only dried plums significantly increased serum levels of insulin-like growth factor-I (IGF-I) and bone-specific alkaline phosphatase (BSAP) activity. Higher levels of both serum IGF-I and BSAP are associated with greater rates of bone formation. Serum and urinary markers of bone resorption, however, were not affected by either dietary regimen. The results of this study suggest that dried plums may exert positive effects on bone in postmenopausal women. Longer duration studies are needed to confirm the beneficial effects of dried plum on bone mineral density (BMD) and the skeletal health of postmenopausal women.
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PMID:Dried plums improve indices of bone formation in postmenopausal women. 1186 Jul 26

The aim of this study was to investigate the effects of tibolone in the prevention of postmenopausal bone loss over 3 years, and to compare these with the effects of sequential hormone replacement therapy. Forty early postmenopausal women were randomized to a 21-day regimen of conjugated equine estrogens (CEE, Premarin) plus sequential medroxyprogesterone acetate (MPA, Prodafem), or tibolone (Livial) daily. In total, 36 women completed 12 months and were considered for the intent-to-treat analysis, 34 completed 24 months and 23 completed 36 months. Main drop-out reasons were: lost to follow-up (n = 9) and minor side-effects (n = 4). Bone mineral density was measured at baseline and after 6, 12, 24 and 36 months, using dual-energy X-ray absorptiometry at the lumbar spine and the upper femur (neck, trochanter, total hip). In both groups, bone loss was prevented. Treatment with tibolone demonstrated significant increases in bone density at the spine (+4.6%; p < 0.01), at the total hip (+3.2%; p < 0.01) and at the trochanter (+4.5%; p < 0.01), whereas the CEE/MPA group showed a non-significant increase of bone mineral density at the lumbar spine (+2.6%) but no increases at the hip. Between-group differences in bone mineral density changes were significant (p < 0.05) for the total hip and the trochanter at 36 months. This increase of bone mineral density was not accompanied by changes in insulin-like growth factor-I (IGF-I) or insulin-like growth factor binding protein-3 (IGFBP-3) in either group. Osteocalcin, alkaline phosphatase and urinary ratios of hydroxyproline/creatinine and calcium/creatinine significantly decreased in both groups. In conclusion, sequential CEE/MPA prevented cortical and trabecular bone loss, with a transient increase of bone mineral density only during the first 6 months. Tibolone not only prevented cortical and trabecular bone loss, but further increased bone mineral density at the lumbar spine and at the hip throughout the 3 years of treatment, suggesting a sustained positive effect on bone mass.
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PMID:A 3-year study of prevention of postmenopausal bone loss: conjugated equine estrogens plus medroxyprogesterone acetate versus tibolone. 1190 45


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