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)

One three-day course of intravenous pamidronate sodium (3-amino-1-hydroxypropylidene-1,1-bisphosphonate), 30 mg/d, in a patient with calcitonin-resistant Paget's disease resulted in the following: marked clinical improvement within two weeks; normalization of urinary hydroxyproline value; fall of serum alkaline phosphatase value (900 to 250 U/L); a rise in serum osteocalcin value by the tenth week that returned to pretreatment levels in the 16th week; transient hypocalcemia with elevation of parathyroid hormone value; reduction in urinary calcium excretion; and improvement in bone scans. No adverse reactions occurred, with the exception of mild and transient hyperpyrexia for 48 hours during pamidronate administration. White blood cell counts did not change and serum interleukin 1 was undetectable before and after treatment with pamidronate. Pamidronate seems to be highly effective in the treatment of Paget's disease of the bone, but its profound effects on mineral and bone metabolism require close monitoring during the short-term period of intravenous treatment.
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PMID:Pamidronate sodium and calcitonin-resistant Paget's disease. Immediate response in a patient. 278 43

The non-collagen proteins of bone are a complex set of molecules that arise from local or exogenous sources. Because bone mineral is an excellent adsorbent, many circulatory and/or cell surface proteins bind to bone, where they may have immediate or subsequent effects. These include the alpha 2-HS-glycoprotein from blood and the potent growth factors TGF-beta, PDGF, IGF-1, FGF-a and -b, and IL-1, derived from both bone and non-bone cells. Furthermore, bone cell membrane proteins such as alkaline phosphatase may be cleaved from the cell surface and entrapped in the bone matrix. Bone is enriched in a variety of enzymes and their inhibitors by similar adsorption processes. Even osteocalcin, a bone cell product, is adsorbed to bone via mineral-binding (Gla) groups. The bone sialoproteins (BSP-I or osteopontin and BSP-II) also bind to the mineral via acidic groups. Because of this phenomenon it is difficult to distinguish whether a given protein's presence in bone is advantageous or merely fortuitous. The bone matrix proper consists of type I collagen and other osteoblast products such as osteonectin (a phosphorylated glycoprotein) and small proteoglycans (PG-I and/or PG-II) which are incorporated into bone collagen fibrils. These proteins may have additional roles in tissue morphogenesis and/or differentiation.
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PMID:Non-collagen proteins in bone. 306 9

The effect of recombinant interleukin 1 Beta (IL-1(beta)) was investigated on osteoblastic cell line MC3T3-E1 cloned from mouse calvaria. IL-1(beta) stimulated cell proliferation which increased cell number and caused dose-related stimulation of DNA synthesis, with a maximal effect at a concentration of 12.5 U/ml; suppressed alkaline phosphatase activity and collagen synthesis maximally at 0.5 and 62.5 U/ml, respectively; and increased the amount of free [3H] hydroxyproline in the cultures, but the amount was quite low. Prostaglandin E2 synthesis was also stimulated dose dependently by the presence of IL-1(beta), with a maximal increase at 2.5 U/ml, at which concentration the prostaglandin E2 level in the medium was 1.61 +/- 0.10 ng/ml. The increased prostaglandin E2 synthesis did not affect either the IL-1(beta)-mediated change in DNA or collagen synthesis or alkaline phosphatase activity. These results extend the possibility that IL-1(beta) is to act as a regulator of bone formation.
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PMID:Effect of interleukin 1 beta on osteoblastic clone MC3T3-E1 cells. 314 Oct 17

Both interleukin-1 alpha (IL-1 alpha) and IL-1 beta are initially translated as approximately Mr 30,000 polypeptides, lacking hydrophobic or signal sequence that could facilitate transmembrane translocation and release of mature IL-1 (Mr 17,500). The current study utilizes an antiserum specific for murine IL-1 alpha in order to investigate membrane associated IL-1 alpha polypeptides and possible postsynthetic modifications of the IL-1 alpha precursor, that might account for its intracellular transport. Cell surface iodination of endotoxin stimulated murine macrophages allowed the detection of IL-1 molecules in size similar to the IL-1 alpha precursor (Mr 33,000). Membrane bound IL-1 alpha was sensitive to degradation by serine esterase activity to yield IL-1 peptides of Mr 16,000 to 18,000. Endotoxin stimulated macrophages, but not unstimulated cells, incorporated 32PO4 into the IL-1 alpha precursor. The phosphate label of the IL-1 alpha precursor is resistant to hydroxylamine and alkaline phosphatase treatment. Released IL-1 is not phosphorylated. Approximately 10% of the phosphorylated IL-1 alpha precursor is membrane bound and associated with fractions enriched in lysosomal vesicles. These data are consistent with a model for mIL-1 expression, in which pro IL-1 alpha is post-synthetically modified to achieve intracellular transport and further suggest that mIL-1 may be a prerequisite for the release of IL-1.
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PMID:Structure and function of membrane IL-1. 326 77

Recombinant human interleukin 1 (rhIL-1)alpha and rhIL-1 beta were examined for their effects on DNA synthesis, cell growth and alkaline phosphatase activity of the mouse osteoblastic cell line MC3T3-E1. The relative activity of rhIL-1 alpha and rhIL-1 beta was compared in terms of the units which induced half-maximal [3H]thymidine uptake into mouse thymocyte cultures exposed to IL-1. Both rhIL-1 alpha and rhIL-1 beta significantly inhibited DNA synthesis and division of the cells in a concentration- and cultivation time-dependent fashion. In contrast, rhIL-1 alpha and rhIL-1 beta markedly increased alkaline phosphatase activity, which is a marker of osteoblastic differentiation. This activity in cells treated with rhIL-1 alpha and rhIL-1 beta increased about 2.0- and 1.7-fold, respectively, compared with that of control cultures. Inhibition of the DNA synthesis and stimulation of alkaline phosphatase activity by both types of rhIL-1 were completely neutralized by treatment with their respective polyclonal antisera. Also, inhibition of DNA synthesis was unaffected by the addition of cyclooxygenase and lipoxygenase inhibitors, and stimulation of alkaline phosphatase activity was unaffected by the addition of indomethacin. These results indicate that both rhIL-1 alpha and rhIL-1 beta have qualitatively similar biological effects on osteoblastic cells. They also suggest that IL-1 is an important modulator of the growth and differentiation of osteoblasts.
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PMID:Effects of recombinant human interleukin 1 alpha and interleukin 1 beta on cell growth and alkaline phosphatase of the mouse osteoblastic cell line MC3T3-E1. 328 95

A mutual antagonism exists between interleukin-1s (IL-1s) as pro-inflammatory and glucocorticoids as anti-inflammatory mediators. This report examines the effects of IL-1 on the induction by dexamethasone of alkaline phosphatase in LEII murine endothelial cells. Dexamethasone increases the specific activity of alkaline phosphatase in a time- and dose-dependent fashion (maximum 14-fold induction at 10(-6) M, IC50 = 10(-8) M), and this induction can be completely inhibited by simultaneous incubation with picomolar concentrations of recombinant human IL-1 alpha or IL-1 beta. This IL-1-mediated antagonism of dexamethasone activity is not due to a down-regulation of glucocorticoid receptors in the cell line used, because the number of receptors and their affinity for dexamethasone is unchanged in IL-1-treated cells. However, induction of alkaline phosphatase by dexamethasone in LEII cells is receptor-mediated, since it can also be inhibited by glucocorticoid-receptor antagonists.
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PMID:Recombinant human interleukin-1 inhibits the induction by dexamethasone of alkaline phosphatase activity in murine capillary endothelial cells. 350 Sep 55

Rat resident peritoneal macrophages in primary culture were found to elaborate a mitogenic factor (or factors) for rat osteoblast-like cells and chondrocytes but not for skin fibroblasts. Growth-promoting activity appeared in the incubation medium within the first 20 hr of macrophage culture and was released in amounts that paralleled the number of macrophages per culture. After their proliferative response, as judged by increases in DNA synthesis and cell number, the osteoblast-like cells became enriched in alkaline phosphatase, an index of osteoblast specialization. The macrophage-derived activity was nondialyzable and heat-stable, and it was eliminated by exposure to trypsin. Inhibition of prostaglandin cyclooxygenase failed to modify its generation. Partial purification (Amicon filter concentration, gel filtration) disclosed principal peaks of activity corresponding to Mr of 43,000 and 10,000. The crude conditioned medium and the Mr 43,000-peak, but not the low-molecular-weight peak, exhibited interleukin 1 activity, as judged by the ability to stimulate the proliferation of mouse thymic lymphocytes. The macrophage-derived growth factor described herein may participate in bone remodeling and repair and in primary bone and cartilage growth.
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PMID:Macrophage-derived growth factor for osteoblast-like cells and chondrocytes. 661 52

Bone remodelling is regulated at the local level by an incompletely elucidated cytokine network. In the present study we have determined the effect of interleukin-4 (IL-4), a cytokine produced by T lymphocytes and other cells, on the activity of murine osteoblasts. IL-4 (0.1-10 ng/ml) did not influence the proliferation rate of the osteoblast-like cell line MC3T3, but inhibited the expression of alkaline phosphatase. In long-term cultures supplemented with ascorbic acid and glycerophosphate such an effect was accompanied by a retardation of matrix mineralization. IL-4 also stimulated M-CSF expression by MC3T3 cells, both at the RNA and bioactivity levels. However, no stimulation of IL-1, IL-6, GM-CSF or PGE2 production was observed. An IL-4-induced inhibition of alkaline phosphatase expression and retardation of mineralization was also found in cultures of primary osteoblast-like cells isolated from neonatal mice calvariae. These results suggest that IL-4, probably released by cells within the bone marrow, may locally influence the activity of bone-forming cells.
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PMID:Interleukin-4 as a bone regulatory factor: effects on murine osteoblast-like cells. 754 94

We investigated expression of several cytokines and growth factors in explants of Pagetic and non-Pagetic bone samples using the technique of reverse-transcription/polymerase chain reaction (RT/PCR). Transcripts for IL-1 alpha and IL-1 beta, TNF-alpha, TNF-beta, IL-6, basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and insulin-like growth factor-I (IGF-I) were found to a variable degree in both Pagetic and non-Pagetic bone samples, but there was no significant difference in the patterns of expression for these factors in Pagetic bone (n = 18) as compared with non-Pagetic bone (n = 51). There was furthermore, no significant difference in the patterns of expression for the various factors studied when patients were subdivided into mild and severe categories of disease activity using markers of bone formation (serum alkaline phosphatase) or bone resorption (osteoclast counts on adjacent biopsy specimens). Although IL-6 and IL-1 have previously been implicated as bone resorbing factors in Pagetic bone, 40% of our patients with severe disease had not detectable IL-6 transcripts, 70% had no detectable IL-1 alpha transcripts and 50% no IL-1 beta transcripts. We conclude that patterns of expression for cytokine and growth factor mRNAs are not disturbed in Paget's disease. Although we cannot exclude the possibility that post-transcriptional processing of the mRNAs may differ in Pagetic and normal bone cells, our data raise the possibility that the abnormalities of bone turnover which are characteristic of active Paget's disease may be due to local elaboration of other, possibly novel osteotropic factors, which stimulate bone formation and resorption.
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PMID:Cytokine and growth factor expression in Paget's disease: analysis by reverse-transcription/polymerase chain reaction. 801 89

Immobilization induces abnormal bone metabolism and rapid decalcification. Measurements of bone mineral content disclosed rapid decalcification, especially in lumbar vertebral and metacarpal bones in our short-term 20-day bed rest study. Many factors could contribute to the marked demineralization. The activities of osteoclasts and osteoblasts were studied by following serum levels of tartrate-resistant acid phosphatase and alkaline phosphatase, biomarkers for osteocyte activity. There were no alterations in these enzymes during bed rest. However, urinary excretion of pyridinium cross-links, resorption markers of bone matrix itself, increased by day 10 with subsequent decrease at day 20. So decalcification was induced without any relation to osteoclast activity. As cytokines strongly modulate the function of osteoclasts, peripheral monocyte release of interleukin 1 alpha and tumor necrosis factor alpha were assayed to determine the contribution to this rapid demineralization. Cytokines were released transiently by day 7 and later rapidly decreased. However, there was no correlation between cytokine release and bone matrix resorption.
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PMID:Metabolic turnover of bone and peripheral monocyte release of cytokines during short-term bed rest. 804 23


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