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)

Prostaglandins are locally produced in a number of tissues in response to a variety of stimuli, including local growth factors and systemic hormones. The present investigation characterizes prostaglandin effects on growth plate chondrocytes. Since cyclic adenosine monophosphate (cAMP) may act as a prostaglandin-stimulated second messenger, the effects of prostaglandins A1, D2, E1, E2, F2 alpha, and I2 (10(-10)-10(-6) M) on cAMP levels and thymidine incorporation were evaluated. The stimulation of cAMP and thymidine incorporation by the various prostaglandin metabolites were dose dependent and highly correlated (r = 0.99, p less than 0.001). The magnitude of the effect varied but was maximal at 10(-6) M for each of the prostaglandins. Prostaglandins of the E series (E1 and E2) were the most potent, causing significant effects at 10(-10) M and with maximal 12- and 13-fold increases in DNA synthesis after a 24 h exposure. Prostaglandins D2 and A1 maximally stimulated thymidine incorporation by 4.7- and 3.1-fold but caused significant increases only at 10(-8) M. Prostaglandins F2 alpha and I2 were the least stimulatory, producing small but significant increases in thymidine incorporation at 10(-6) M (30 and 100% stimulations). A causal relationship between cAMP and thymidine incorporation was further verified by the ability of dibutyryl-cAMP to increase DNA synthesis. Long-term chondrocyte cultures treated continuously with PGE2 demonstrated an increase in cell number, confirming the proliferative effect. Indomethacin did not alter the potent dose-dependent stimulations of chondrocyte DNA synthesis by TGF-beta 1, basic FGF, or PTH, indicating that these known mitogens act independently of prostaglandin metabolism. PGE2 was further examined for its effects of matrix synthesis. PGE2 inhibited collagen synthesis with a maximal 42% decrease but did not alter noncollagen protein synthesis. In contrast, PGE2 maximally increased sulfate incorporation by 35% and caused a small dose-dependent inhibition in alkaline phosphatase activity. Thus, prostaglandins alter DNA and matrix synthesis in growth plate chondrocytes and may have an important role in chondrocyte metabolism in the growth plate, fracture callus, and other areas of endochondral ossification.
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PMID:Influence of prostaglandins on DNA and matrix synthesis in growth plate chondrocytes. 131 4

Transforming growth factor-beta (TGF beta) produced by osteoblasts is present in high levels in bone and influences bone formation, replication of bone cells, and expression of osteoblast protein products. Interactions between bone active hormones and locally released and activated TGF beta were studied by examining the influence of TGF beta preincubation on PTH, calcitonin (CT), and vitamin D receptors in an osteoblastic cell line (UMR 106-06). Preincubation of UMR 106-06 cells with 1 ng/ml TGF beta for 3 days increased specific binding of [125I]PTH-related protein (PTHrP)(1-84) to 140% of that in control cells, but [125I]salmon CT binding decreased to 50% of controls. Binding isotherms indicated that the changes in binding were due to altered receptor numbers since affinities for 125I-labeled PTH and CT remained unchanged. The effect on receptor levels was time dependent, requiring 24 h preincubation with TGF beta for measurable changes, and dose dependent, with maximal effects seen with 1 ng/ml TGF beta. Binding of [3H]1,25(OH)2 vitamin D3 was increased to 130% of control in cytosolic extracts of UMR 106-06 cells pretreated for 3 days with 1 ng/ml TGF beta. Scatchard plots suggested an increase in receptor number without change in affinity. The adenylate cyclase response to PTH increased to 150% of control cells after 3 days of treatment with 1 ng/ml TGF beta; however, the adenylate cyclase response to CT was little changed. Forskolin- and cholera toxin-stimulated adenylate cyclase responses were increased by TGF beta treatment to 130-160% of control, indicating an increase in the stimulatory subunit of the G protein. Increased abundance of both Gs and Gi proteins were indicated by increased cholera toxin- or pertussis toxin-dependent [32P] NAD ribosylation of 47-kilodalton (kDa) and 42-kDa or 40-kDa proteins, respectively, in TGF beta-treated cells. Our data support a complex regulatory effect of TGF beta on UMR 106-06 cells with increases in PTH receptors, vitamin D receptors, and G proteins, whereas there is an apparent down-regulation of CT receptors. TGF beta might induce a more differentiated osteoblast phenotype of these cells, which already express differentiated features such as high alkaline phosphatase activity, PTH and vitamin D receptors, and collagenase production. Since low doses of PTH stimulate bone formation in vivo, TGF beta released or activated at sites of new bone formation might locally modulate PTH activity be allowing increased PTH receptor and postreceptor effectiveness.
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PMID:Transforming growth factor-beta modulates receptor binding of calciotropic hormones and G protein-mediated adenylate cyclase responses in osteoblast-like cells. 132 61

This study evaluates the effect of intravenous calcitriol on parathyroid function and ionized calcium-PTH sigmoidal curve obtained during low- and high-calcium haemodialysis in 10 patients with osteitis fibrosa whose secondary hyperparathyroidism was refractory to conventional therapy. After 4 months of intravenous calcitriol, serum ionized calcium increased from 1.28 +/- 0.08 to 1.37 +/- 0.11 mmol/l (P less than 0.001), serum phosphate from 1.54 +/- 0.18 to 1.79 +/- 0.4 mmol/l (P NS), serum calcitriol from 16.7 +/- 9.9 to 34.3 +/- 6.4 pg/ml (P less than 0.001), while alkaline phosphatase decreased from 366 +/- 340 to 226 +/- 180 IU/l (P less than 0.05), osteocalcin from 46.4 +/- 20 to 34.5 +/- 15.3 ng/ml (P less than 0.05), and basal intact PTH from 1069 +/- 700 to 305 +/- 270 (P less than 0.01). Basal PTH started to decrease after 1 month of treatment prior to the increase in the ionized calcium. Because of hypercalcaemia the dialysate calcium was decreased from 1.75 to 1.5 mmol/l in three of five patients on haemodialysis, and calcium-containing solutions were replaced by calcium-free fluids in four of five patients on haemodiafiltration. Calcitriol dose, at the first month of therapy was 5.6 +/- 0.8 micrograms/week, but it was successively decreased because of hypercalcaemia to a final dose of 3.6 +/- 1.3 micrograms/week. After intravenous calcitriol the ionized calcium-PTH sigmoidal curve shifted to the left and downward. Maximally stimulated PTH and maximally inhibited PTH obtained during low- and high-calcium dialysis significantly decreased, as well as the ratio of basal PTH/PTHmax and the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of chronic intravenous calcitriol on parathyroid function and set point of calcium in dialysis patients with refractory secondary hyperparathyroidism. 132 15

We performed dynamic parathyroid function tests, with generation of parathyroid hormone/ionized calcium (PTH/iCa) response curves, obtained during sequential hypercalcaemic and hypocalcaemic dialysis, on six haemodialysis patients before and after 4-weekly 'pulse' doses of oral calcitriol. There were no significant changes in the pretreatment, 2-week and 4-week values of blood ionized calcium, serum total calcium, phosphate, and alkaline phosphatase. PTH decreased significantly after 4 weeks of treatment with calcitriol (P less than 0.03), and the post-treatment PTH/iCa curves were all displaced leftwards and downwards, indicating a marked inhibitory effect of calcitriol on parathyroid responsiveness across and beyond the physiological range of calcaemia. The mean shift of the PTH/iCa relationship was equivalent to a reduction of iCa of 0.2 mM for any given concentration of PTH, and conversely to a 70% reduction of PTH for any given blood iCa. The results suggest that wide spacing of oral 'pulse' doses of calcitriol can achieve favourable modification of the PTH/iCa relationship, and that dosing interval and dose size, rather than route of administration, may be the major determinants of the previously reported superiority of intravenous over daily oral calcitriol regimens.
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PMID:'Pulse' oral calcitriol in uraemic patients: rapid modification of parathyroid response to calcium. 132 16

Fetal antigen 2 (FA2) was found within the cytoplasm of osteoblasts and in osteoid material, in a bone biopsy with morphological changes of renal osteodystrophy. An ELISA technique for FA2 quantification was developed, and the specificity confirmed by comparison with electroimmunoassay. The intra- and interassay coefficient of variations (%) were 8.3 and 9.7 respectively, and the detection limit 0.0004 arbitrary units FA2/1 using second-trimester human amniotic fluid as reference (1 AU FA2/1). FA2 was detected in serum-free supernatants from osteoblast cultures. Following size chromatography, the FA2 distribution (two peaks eluted corresponding to Mw 30 kDa and 100 kDa) in serum from a patient with chronic renal failure complicated with secondary hyperparathyroidism and in human amniotic fluid were identical. Probably due to the detection limit, only one peak fraction (30 kDa) was seen in normal human serum. Significantly greater FA2 concentrations were found in sera (n = 14) from patients with chronic renal failure (median: 11.9 mAU FA2/1; range: 5.2-49.0 mAU FA2/1) compared to normal healthy individuals (n = 23) (median: 4.1 mAU FA2/1; range 2.4-9.4 mAU FA2/1) (P less than 0.00001). A close correlation was found between serum FA2 and alkaline phosphatase (R(s) = 0.761; P = 0.006), c-terminal fraction of PTH (R(s) = 0.872; P = 0.003) and intact PTH(1-84) (R(s) = 0.904; P = 0.011) in the haemodialysis patients. These data indicate that FA2 is synthesized by osteoblasts and may represent a new marker for metabolic bone changes.
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PMID:Quantification of fetal antigen 2 (FA2) in supernatants of cultured osteoblasts, normal human serum, and serum from patients with chronic renal failure. 132 37

The effects of tissue maturation on the cellular composition and biochemical characteristics of bone were studied in neonatal, young adult, and aging mice. Osteoblast subclasses were isolated on Percoll density gradients. Neonatal calvariae consisted almost exclusively of cells banding at low and intermediate buoyant density. High buoyant density cells constituted 5-10% of total cells at 10 days of age but increased to 50-60% by 5 weeks of age. These latter cells were released late during collagenase digestion. This indicates that they arise from the deeper layer of bone. For this reason, we consider them putative osteocytes. We established that constitutive secretion of IGF-I and TGF-beta and activities of cellular alkaline phosphatase paralleled those of the tissue of origin in all cell groups and was highest in cells of intermediate buoyant density. These activities declined rapidly after cessation of growth at 5 weeks of age in both bone and isolated cells. Between 5 and 8 weeks of age, the hormonal response to PTH also declined dramatically. The maximum cAMP induced by PTH declined by about 70% in highly responsive cells of intermediate buoyant density and fell to insignificant levels in cells of high buoyant density. We found that a cyclic AMP response to PTH was positively correlated with stimulated secretion of IGF-I by this hormone in cells from animals of all ages. Despite their inability to respond to PTH with increases in cAMP and IGF-I, adult bone cells of high buoyant density continued to respond to PTH with increases in the secretion of TGF-beta.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Maturation-associated changes in the cellular composition of mouse calvariae and in the biochemical characteristics of calvarial cells separated into subclasses on Percoll density gradients. 132 39

The effects of the immunosuppressive drug cyclosporin A (CsA) were evaluated on ROS 17/2.8 cells in vitro. ROS cells were treated with CsA (0, 0.5, 1.0, 5.0 micrograms/ml) for 3 days with and without bovine parathyroid hormone (bPTH) (1-34) 10 nM. CsA at 0.5, 1.0, 5.0 micrograms/ml without PTH and at 5.0 micrograms/ml in the presence of PTH significantly inhibited proliferation, as determined by a tetrazolium colorimetric assay. In addition, ROS cell number was significantly reduced at 3 and 4 days with CsA (5.0 micrograms/ml) without affecting cell viability. Incorporation of [3H]-thymidine into DNA was significantly reduced by 3.0 and 5.0 micrograms/ml CsA after 12 and 24 hours exposure. Basal and 1,25-dihydroxyvitamin D3-stimulated alkaline phosphatase levels in confluent ROS cells were reduced (P less than 0.05) with CsA (1.0 and 3.0 microgramS/ml). Pretreatment of ROS 17/2.8 cells with CsA did not alter PTH-stimulated cAMP levels or [125I]-PTHrP binding to ROS cells. CsA treatment of ROS 17/2.8 cells induced a spindle-shaped appearance with loss of attachment in confluent cultures. When ROS cells were cultured in CsA-containing media, cellular attachment at 6 and 12 hours was reduced (P less than 0.05) compared with untreated ROS cells. These findings indicate that CsA was capable of inhibiting proliferation, cell number, mitogenesis, alkaline phosphatase levels, and cell attachment of ROS cells without affecting PTH binding or cAMP levels. This direct effect of CsA on osteoblasts may be important in changes of bone remodeling observed in CsA-treated humans and animals.
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PMID:Effects of cyclosporin A on rat osteoblasts (ROS 17/2.8 cells) in vitro. 133 Feb 39

The use of intestinal segments in the urinary tract can cause metabolic changes that depend on the intestinal segment utilized. The severity of these changes basically depends on the area of the intestinal mucosa in contact with urine, the duration of exposure to urine and renal function. The length of time the intestinal mucosa is in contact with urine largely depends on the surgical technique employed. It is longer for the reservoirs, intestinal neobladders and ureterosigmoidostomies than for the intestinal conduits with cutaneous urinary diversion and therefore carry a higher incidence of metabolic changes. Jejunal urinary diversion causes metabolic acidosis with hypochloremia, hyponatremia, hyperpotassemia, azotemia and dehydration in at least 50% of the cases. Ileal and colonic urinary diversion can cause metabolic acidosis, although the incidence is significantly less. Acidosis presents with hyperchloremia, hyperammonemia, hypersulfatemia, increased osmolality and uremia with normal creatininemia and a tendency to develop hypocalcemia, hypophosphoremia and hypomagnesemia. Recent studies performed in our service show that acidosis is basically due to the secretion of sodium bicarbonate by the intestinal segment used in the urinary tract, which causes water-salt depletion that is compensated by secondary hyperaldosteronism. Mild chronic acidosis is neutralized via the respiratory system and by the bone buffers, which leads to bone remodelling manifested by the significant increase of serum alkaline phosphatase levels and increased calciuria. These calcium phosphate changes, although statistically significant, do not appear to be important since they were not accompanied by changes of serum PTH levels, 25 and 1-25-cholecalciferol. Nicotinic acid as inhibitor of cyclic AMP synthesis failed to correct metabolic acidosis in the patients with transileal diversion.
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PMID:[Physiopathology and treatment of metabolic changes in transintestinal urinary diversions]. 133 44

A predictable animal model with skeletal remodeling characteristics similar to those of humans is needed to facilitate the understanding of the mechanism of postmenopausal osteoporosis. We have utilized the ovariohysterectomized (Ovh) dog to examine cellular and biochemical responses to estrogen depletion and PTH stimulation. Histomorphometric measurements of bone biopsies taken prior to (first biopsy) and five months after the operation (second biopsy) showed no significant differences in static and dynamic parameters. Bone mineral density of the excised vertebrae displayed the same values between the two groups six months after surgery. Between the second biopsy and sacrifice, two infusion studies were performed. A two-hour infusion of EDTA followed by a two-hour recovery period elicited a rapid response in PTH production, highly correlated to the changes in ionized calcium, but no significant difference in response was observed between Sham and Ovh groups. A short-term (24-h) infusion of 1-34 hPTH increased circulating ionized calcium and 1,25-(OH)2-D levels to a similar extent in both groups. The levels of alkaline phosphatase were constant and both groups showed a small but nonsignificant increase in osteocalcin. The lack of sizable responses in histomorphometric, bone mass, and biochemical parameters may limit the utility of dogs for the study of cancellous bone loss in ovarian-dysfunction osteoporosis.
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PMID:Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariohysterectomized dogs. 138 70

To evaluate bone loss in renal osteodystrophy, we measured total and regional (head, trunk, pelvis, leg and arm) bone mineral density (BMD) by dual photon absorptiometry in 72 patients on maintenance hemodialysis (HD). We also examined the validity of serum carboxy-terminal parathyroid hormone (C-PTH) and intact-PTH as an indicator of secondary hyperparathyroidism. Total BMD correlated inversely with age in female patients (r = -0.57, p less than 0.01), but not in male patients. Female patients older than 50 years were omitted from analysis to exclude the effect of menopause on bone. Among clinical and biochemical parameters, only trunk BMD correlated inversely with the duration of HD (r = -0.26, p less than 0.05). Head, trunk and total BMD correlated inversely with serum alkaline phosphatase, C-PTH and intact-PTH, while pelvis BMD did not. Leg and arm BMD also correlated inversely with serum intact-PTH, but not with serum C-PTH. The serum level of C-PTH correlated positively with the duration of HD (r = 0.40, p less than 0.005), while intact-PTH did not. As compared with 18 control male volunteers aged 25-42 years, trunk, pelvis, leg, arm and total BMD were significantly lower in male patients on HD aged 22-49 years, whereas head BMD did not differ significantly between the two groups. The percent decrease of BMD was most prominent in the trunk (-19.6%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Total and regional bone mineral density by dual photon absorptiometry in patients on maintenance hemodialysis. 139 68


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