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)

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2 +/- 2.0 years) all of whom had bone ages less than or equal to 12 years (10.0 +/- 1.4 years), a height standard deviation score of less than -2.5 (-4.9 +/- 1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40 ml/min per 1.73 m2 (51 +/- 6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7 +/- 2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5 +/- 1.6 cm/year pre therapy, 8.5 +/- 1.4 cm/year post therapy, P less than 0.001) and percentage of expected growth velocity for bone age (67 +/- 31% pre therapy, 163 +/- 27% post therapy, P less than 0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of growth hormone administration in pediatric renal allograft recipients. 153 44

Recent studies have demonstrated that growth hormone (GH)-deficient adults have a markedly decreased bone mineral content compared to healthy adults. However, there are conflicting results regarding the effects of GH treatment on bone mineral content in GH-deficient adults. Therefore, we evaluated the effect of GH treatment on a marker of bone formation (bone alkaline phosphatase), hepatic excretory function and distal forearm bone mineral content in GH-deficient adults. Growth hormone was administered subcutaneously in 21 adults (13 males and 8 females) with GH deficiency of childhood onset for 4 months in a double-blind, placebo-controlled GH trial, while 13 of the patients then received further GH for an additional 14 months. Serum insulin-like growth factor I (IGF-I) increased significantly from 100 to 279 micrograms/l and IGF binding protein-3 (IGFBP-3) from 1930 to 3355 micrograms/l after 4 months of GH treatment (p < 0.0001). In addition, the molar ratio between IGF-I and IGFBP-3 increased significantly from 0.22 to 0.33 after GH treatment (p < 0.0001). Bone alkaline phosphatase increased significantly from 38.6 to 92.9 U/l during GH therapy in male patients (p < 0.0001), whereas liver-derived alkaline phosphatase was unaltered by GH. In the females, the increase in bone alkaline phosphatase did not reach statistical significance (19.1 vs 40.0 U/l, p = 0.06). The GH-induced increase in bone alkaline phosphatase correlated significantly with the increase in serum IGFBP-3 (r = 0.46, p = 0.04) but not with the increase in serum IGF-I (p = 0.16).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth hormone (GH) treatment increases serum insulin-like growth factor binding protein-3, bone isoenzyme alkaline phosphatase and forearm bone mineral content in young adults with GH deficiency of childhood onset. 751 28

Bone mineral metabolism and mineralization before and during treatment were studied in 10 girls aged 6.9-8.4 years affected by central precocious puberty and treated with gonadotrophin-releasing hormone agonist (GnRHa) leuprolide acetate depot, in order to understand better the consequences of oestrogen deficiency and the reduction of growth hormone (GH)-insulin-like growth factor I (IGF-I) axis activity. Before and after 12 months of therapy, the patients underwent a clonidine stimulation test and a 4-day calcitriol osteoblast stimulation test. On day 0, day 5 and at 3-month intervals thereafter, serum calcium, phosphate, alkaline phosphatase, IGF-I, IGF binding protein 3 (IGFBP-3), GH, GH binding protein and osteocalcin levels were measured; urinary calcium, phosphate and hydroxyproline levels were evaluated in fasting spot samples. Trabecular and cortical bone mass variations, measured by dual X-ray absorptiometry in the lumbar spine and by dual photon absorptiometry in the radius, respectively were evaluated before the start and after 12 months of therapy. During treatment, a decrease of serum oestradiol levels from pubertal to prepubertal levels was observed. The GH peak following clonidine diminished significantly after 1 year. Growth hormone binding protein showed a slight increase, and IGF-I and IGFBP-3 decreased, although not significantly. Osteocalcin levels decreased significantly after 9 and 12 months of treatment, but they did not change significantly after calcitriol load, either before or after GnRHa therapy. Urinary hydroxyproline decreased significantly after 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone mineral metabolism in girls with precocious puberty during gonadotrophin-releasing hormone agonist treatment. 758 63

Growth hormone (GH) increases bone formation in vivo in pigs. The capacity of GH and its mediator insulin-like growth factor-I (IGF-I) to influence bone cell proliferation and differentiation was investigated in cells isolated from trabecular and cortical bone of growing pigs, from fetal pig bone and from newborn rat calvaria. GH enhanced the proliferation of confluent rat cells but did not affect that of either confluent or subconfluent porcine cells from trabecular, cortical or fetal bone. IGF-I increased the proliferation of confluent rat cells and subconfluent pig cells. GH slightly inhibited alkaline phosphatase (ALP) activity in pig cells of the three origins while IGF-I increased it in cortical cells. Collagen synthesis by pig cells was stimulated by IGF-I but not by GH. These results suggest that GH does not stimulate bone forming cells in pigs, and that GH and IGF-I affect cultured bone cells differently depending on the species or bone type they were isolated from.
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PMID:Effects of growth hormone and insulin-like growth factor-I on the proliferation and differentiation of cultured pig bone cells and rat calvaria cells. 785 85

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.
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PMID:Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly. 823 7

Longitudinal growth is a result of proliferation and differentiation of chondrocytes in the growth plate. Growth hormone (GH) stimulates longitudinal growth, and GH receptors have been shown on growth plate chondrocytes, but the effects of GH on chondrocytes of different cell layers are not clear. To study the effect of GH on chondrocyte activity, in situ biochemical techniques were used to measure enzyme activities, which are associated with cell differentiation (alkaline phosphatase [ALP]) and osteoclast activity (tartrate-resistant acid phosphatase [TRAP]), within single cells of the growth plate. Uptake of bromodeoxyuridine (BrdU) was used as a parameter for proliferative activity. In addition, glucose-6-phosphate dehydrogenase (G6PD) was measured since increased proliferation has been associated with increased G6PD activity. The role of GH was studied in a model of isolated GH deficiency (dwarf rat) and complete pituitary deficiency (hypophysectomized rat). Groups of GH-deficient dwarf rats were infused with recombinant human GH in either a continuous or a pulsatile manner, since the pattern of GH secretion is an important regulator of growth in the rat. After 7 days, G6PD activity in proliferative chondrocytes and TRAP activity in osteoclasts was increased, while ALP activity in hypertrophic chondrocytes was decreased. GH not only increased the number of chondrocytes that incorporated BrdU but also the total number of chondrocytes in the proliferative zone; therefore, its ratio, the labeling index (an indicator of proliferative rate), was not increased. The widths of the proliferative and hypertrophic zones were increased by both patterns of GH administration. The width of the resting zone was unaffected by continuous GH but decreased by pulsatile GH. ALP and TRAP activities were, respectively, higher and lower in hypophysectomized rats compared with the GH-deficient animals. Hypophysectomized rats had smaller growth plates than dwarf rats with a disproportionally wide resting zone, which, like BrdU uptake, was not affected by GH. GH treatment resulted in increased TRAP and decreased ALP activity. These results indicate that GH stimulates the commitment of chondrocytes within the resting/germinal layer to a proliferative phenotype (as opposed to stimulating the rate of chondrocyte proliferation) but only in the presence of other pituitary hormones. Furthermore, this study shows that enzyme activities within single chondrocytes and osteoclasts are GH-sensitive. The extent to which these effects are direct or mediated by systemic or local growth factors remains to be clarified.
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PMID:Single cell enzyme activity and proliferation in the growth plate: effects of growth hormone. 885 46

Growth hormone (GH) is a powerful anabolic hormone with a broad spectrum of action that has been assessed with three general parameters: auxological to assess the growth response; biochemical to measure anabolic effects; and body composition. In childhood, linear growth response is assessed with height, short-term changes in height velocity (HV), and attainment of final adult height, which may not be concordant. In both children and adults, the biochemical indices utilized to predict and/or monitor response to GH therapy have included: (1) nonspecific indices: glucose, insulin, urea, protein synthesis, lipid metabolism, and lipoproteins; (2) more specific indices of the GH-IGF axis: GH binding protein, IGF-I, IGFBP-3, and acid-labile subunit; or (3) indices of bone and mineral metabolism: calcium, phosphate, bone alkaline phosphatase, osteocalcin, propeptides of procollagen type I and III, and bone mineral content. For body composition, body mass index, total body % fat, total body or extracellular water, and bone mineral density have been addressed most frequently. Modest changes with wide variability have been observed with most measurements. GH dose is a very significant positive factor for all parameters. Few of the currently available tests can reliably predict and/or monitor response to GH therapy. Of these, serum IGF-I appears to offer the best integrated indicator of the action of GH throughout all age groups.
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PMID:How do we best measure growth hormone action? 943 38

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). We determined the effect of chronic administration of the GH secretagogue, MK-677, on serum IGF-I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double-blind, placebo-controlled clinical studies lasting 2-9 weeks. Urine was collected for determination of N-telopeptide cross-links (NTXs), a marker of bone resorption, and blood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF-I levels pre- and post-treatment. Dose response data were initially obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg of MK-677 or placebo for 2 weeks (n = 10-12/group). Treatment with 10 mg and 25 mg of MK-677 for 2 weeks increased mean urine NTXs 10% and 17%, respectively (p < 0.05 vs. placebo). Additionally, 50 healthy elderly subjects received either placebo (n = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily for 2 weeks followed by 50 mg daily for 2 weeks. MK-677 increased mean serum osteocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK-677 increased serum IGF-I levels significantly (55-94%). Subsequently, the biological effects of MK-677 were studied in 105 elderly subjects who met objective criteria for functional impairment. Subjects were randomized to receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK-677 daily for an initial 2 weeks followed by 25 mg of MK-677 daily for the next 7 weeks(n = 63 on MK-677 and n = 28 on placebo completed 9 weeks of therapy). Treatment with MK-677 (all MK-677 groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p < 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p < 0.05 vs. placebo). The change from baseline serum osteocalcin correlated with the change from baseline serum IGF-I in the MK-677 group (r = 0.37; p < 0.01). In conclusion, once daily dosing with MK-677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.
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PMID:Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group. 1040 19

Growth hormone releasing hormone (GHRH) receptors are members of the G-protein receptor family that use cAMP as a second messenger. A human fetal kidney 293-derived cell line stably expressing the porcine GHRH receptor (pGHRHr/293 cells) and a cAMP-responsive reporter system were used to develop a bioassay for human GHRH. The reporter system (ph alpha180SEAP) was constructed by subcloning the tandem cAMP response elements from the human glycoprotein hormone alpha subunit gene promoter (h alpha180) upstream from the secreted alkaline phosphatase cDNA of reporter plasmid pSEAP-Basic. To generate a stable cell line expressing both the GHRH receptor and SEAP reporter system, a DNA fragment from pPUR that confers puromycin resistance was subcloned downstream from the reporter construct of ph alpha180SEAP. Tranfection of ph alpha180SEAPpur into pGHRHr/293 cells yielded pGHRHr/SEAP/293 cell lines that responded to recombinant GHRH with dose-dependent increases in SEAP activity. The GHRH receptor-SEAP reporter bioassay was compared to a conventional bioassay using cultured rat anterior pituitary cells. Synthetic and recombinant GHRH induced a 3.1-fold increase in growth hormone release by rat pituitary cells with ED50's of 3.6 and 2.2 x 10(-10) M, respectively. Recombinant GHRH was 1.7 +/- 0.7 times more potent than synthetic GHRH in the pituitary cell bioassay. In an analogous experiment, pGHRHr/SEAP/293 cells responded to synthetic and recombinant GHRH with a 9.1-fold increase in SEAP activity. The ED50's were 7.8 and 4.3 x 10(-11) M, respectively, with recombinant GHRH being 1.8 +/- 0.1 times more potent than the synthetic preparation. Thus, the GHRH receptor-SEAP reporter bioassay is a sensitive, accurate, precise and efficient method for measuring GHRH biological activity.
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PMID:Bioassay for growth hormone releasing hormone (GHRH) using a recombinant receptor and cAMP-responsive reporter system. 1041 1

Growth hormone (GH) regulates transcription factors associated with c-fos, including C/EBPbeta. Two forms of C/EBPbeta, liver-activating protein (LAP) and liver inhibitory protein (LIP), are dephosphorylated in GH-treated 3T3-F442A fibroblasts. GH-induced dephosphorylation of LAP and LIP is reduced when cells are preincubated with phosphatidylinositol 3'-kinase (PI3K) inhibitors. GH activates Akt and inhibits glycogen synthase kinase-3 (GSK-3). Lithium, a GSK-3 inhibitor, increases GH-dependent dephosphorylation of LAP and LIP. Both are in vitro substrates of GSK-3, suggesting that GSK-3 inactivation contributes to GH-promoted dephosphorylation of C/EBPbeta. Alkaline phosphatase increases binding of LAP homodimers and decreases binding of LIP homodimers to c-fos, suggesting that dephosphorylation of C/EBPbeta modifies their ability to bind DNA. Both alkaline phosphatase- and GH-mediated dephosphorylation comparably increase binding of endogenous LAP in 3T3-F442A cells. In cells overexpressing LAP and GSK-3, LAP binding decreases, suggesting that GSK-3-mediated phosphorylation interferes with LAP binding. Expression of constitutively active GSK-3 reduced GH-stimulated c-fos promoter activity. These studies indicate that PI3K/Akt/GSK-3 mediates signaling between GH receptor and the nucleus, promoting dephosphorylation of C/EBPbeta. Dephosphorylation increases binding of LAP complexes to the c-fos promoter and may contribute to the participation of C/EBPbeta in GH-stimulated c-fos expression.
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PMID:Growth hormone regulates phosphorylation and function of CCAAT/enhancer-binding protein beta by modulating Akt and glycogen synthase kinase-3. 1127 38


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