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)

By use of quantitative histochemistry, effects of interleukin 1 (IL1) on the differentiation of osteoblasts derived from neonatal rabbit calvaria were studied. The results showed that IL 1 inhibits the alkaline phosphatase activity in the cultured osteoblasts. Also, both quantitative immunohistochemistry study and radioimmunoassay study showed that IL-1 has the ability to stimulate osteocalcin production and secretion in the cultured osteoblasts. Our results suggest that IL 1 plays a role in the regulation of osteoblastic differentiation, and in the end inhibits the calcification of bone matrix.
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PMID:[Effects of interleukin-1 on the differentiation of osteoblasts]. 959 57

Lymphocytes are implicated in the pathogenesis of bone disease in chronic inflammation, osteoporosis, transplantation and osteopetrosis. The effects of lymphocytes and lymphocyte-conditioned medium on bone-resorbing activity and osteoclast function have been well studied, but there are few studies of the effects of LCM on bone formation and osteoblast function. The effects of LCM on the function of the MG-63 human osteosarcoma cell line were studied, which, when stimulated with 1,25-(OH)2D3, demonstrates many of the properties of the mature human osteoblast. Lymphocytes contain oestrogen receptors and the model was also used to test the hypothesis that the effects of oestrogen on bone cells may be mediated indirectly via lymphokines. Lymphokines were measured by ELISA in human lymphocyte conditioned medium (LCM) collected following incubation of mixed lymphocytes with or without stimulation for 72 h. Unstimulated LCM increased proliferation of MG-63 cells and this increase was not affected by neutralization of interleukin 1 (IL-1), IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF), lymphotoxin alpha, or interferon gamma (IFN-gamma). Phytohaemagglutinin-stimulated LCM decreased proliferation of MG-63 cells, as well as induced expression of IL-6 mRNA, increased alkaline phosphatase production, and inhibited osteocalcin production. The decrease in proliferation was abolished by neutralization of IFN-gamma but was unaffected by neutralization of IL-1, IL-2, IL-3, IL-4, IL-6, GM-CSF, TNF, or lymphotoxin alpha. Neutralization of IFN-gamma in stimulated LCM also partially inhibited the increase in alkaline phosphatase production but had no effects on the decrease in osteocalcin production. Although oestrogen inhibited lymphocyte proliferation, the effects of LCM collected from lymphocytes in the presence of oestrogen on MG-63 cell proliferation and function was no different than the effects of LCM collected in the absence of oestrogen. LCM has multiple effects on MG-63 cell function and gene expression. Lymphocyte stimulation during the preparation of LCM further modulates these effects. Although partially mediated by IFN-gamma, the effects of LCM on these cells cannot be completely explained by individual component lymphokines. This may have implications for understanding the pathophysiology of bone loss in inflammatory disorders as well as possible feedback loops of locally generated cytokines in bone.
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PMID:Effects of human lymphocyte-conditioned medium on MG-63 human osteosarcoma cell function. 972 33

Estrogen replacement therapy (ERT) is known to prevent bone loss following the menopause, but the mechanism for this is unclear. Estrogen may suppress the secretion of certain bone-resorbing cytokines. The aim of this study was to assess the effect of ERT on the levels of cytokines measured in peripheral blood. We measured cytokines in 10 postmenopausal women (ages 56-59, 3-9 years since menopause) treated with ERT and 10 age-matched (54-59 years, 4-10 years since menopause) untreated women as controls. Samples of blood were taken and used for mononuclear cell cultures, whole blood (WB) cultures, and the separation of serum. The cultures were treated with lipopolysaccharide (LPS; 500 ng/ml) and hydrocortisone (10(-6) M). The conditioned medium from cultures and the serum were then assayed for interleukin-6 (IL-6), IL-1alpha IL-1beta, IL-1 IL-1ra, tumor necrosis factor alpha (TNF-alpha), and granulocyte macrophage colony stimulating factor (GM-CSF) by enzyme-linked immunosorbent assay. M-CSF and the soluble cytokine receptors soluble IL-6 receptor (sIL-6r) and soluble TNF receptor type 1 (sTNFr1) were also measured in serum and M-CSF in stimulated WB cultures. Measurements were corrected for mononuclear cell count. We also measured serum bone-specific alkaline phosphatase (ibAP) in all subjects. We found that LPS stimulated secretion of all cytokines both in WB and isolated cell cultures, and that this was attenuated by hydrocortisone. A significantly higher ratio of IL-1beta/IL-1ra (p = 0.02) in LPS stimulated WB cultures was seen in the untreated women. Levels of IL-1beta and IL-1alpha measured in WB cultures were lower and IL-1ra was higher in the ERT-treated group but these results were not significant. BAP was higher in the untreated group (p = 0.005) and correlated with IL-alpha/IL-1ra in the whole group (r = 0.49, p = 0.03). Results of other measurements showed no significant differences between groups. We conclude that estrogen may prevent bone loss following the menopause by altering the balance between IL-1beta and IL-1ra.
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PMID:Effects of estrogen therapy of postmenopausal women on cytokines measured in peripheral blood. 978 46

In previous research, we were able to demonstrate that a seven amino acid residue peptide (VITFFSL), designed as an antisense peptide of the beta-bulge trigger loop region of interleukin 1beta (IL-1beta) (QGEESND; residues 48-54 [mature protein sequence]), was able to interact with IL-1 specifically and inhibit the response to IL-1 in an in vitro bioassay. The evidence was consistent with a specific interaction ocurring between antisense peptide and the trigger loop region. On the basis that antisense peptides are able to interact with their corresponding sense peptide sequences as a result of their mutually complementary hydropathic profiles (Fassina G., Verdoliva, A., Cassani, G., Melli, M., 1994. Binding of type I IL-1 receptor fragment 151-162 to IL-1. Growth Factors 10, 99-106; Maier, C.C., Moseley, H.N.B., Zhou, S., Whitaker, J.N., Blalock, J.E., 1994. Indentification of interactive determinants on idiotypic-anti-idiotypic antibodies through comparison of their hydropathic profiles. Immunomethods 5, 107-113), we devised a computer program (FINDH) to search the amino acid residue sequence of interleukin-1 type 1 receptor (IL-1 R1) for peptide motifs possessing hydropathic complementarity to the trigger loop sequence. The most complementary "best-fit peptide" motif (LITVLNI) was located in the third extracellular domain of IL-1 R1. A best-fit peptide corresponding to this motif was synthesised and found to bind to IL-1beta as well as inhibit the response to IL-1 in two independent in vitro bioassays (monitoring IL-1 dependent serum amyloid A synthesis and IL-1 dependent alkaline phosphatase activity, respectively). A second peptide motif (VIEFITL) was identified and the corresponding peptide synthesised along with a reordered version (LTILINV) of the best fit peptide. Both failed to bind measurably with IL-1beta or inhibit the response to IL-1 in the two bioassays. This best fit peptide behaved very similarly, in terms of IL-1 binding and inhibition behaviour, to the original trigger loop antisense peptide. Reference to the recently released X-ray crystal structure of IL-1beta and the IL1-R1 extracellular domain shows that the best fit peptide motif in IL-1 R1 is not apparantly interacting with the IL-1 trigger loop, although both are close in space. The intriguing possibility exists that the best fit peptide motif could represent an alternative site for IL-1beta receptor interaction which has not thus far been identified.
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PMID:A search within the IL-1 type I receptor reveals a peptide with hydropathic complementarity to the IL-1beta trigger loop which binds to IL-1 and inhibits in vitro responses. 1069 16

Radiation of the esophagus of C3H/HeNsd mice with 35 or 37 Gy of 6 MV X rays induces significantly increased RNA transcription for interleukin 1 (Il1), tumor necrosis factor alpha (Tnf), interferon gamma inducing factor (Ifngr), and interferon gamma (Ifng). These elevations are associated with DNA damage that is detectable by a comet assay of explanted esophageal cells, apoptosis of the esophageal basal lining layer cells in situ, and micro-ulceration leading to dehydration and death. The histopathology and time sequence of events are comparable to the esophagitis in humans that is associated with chemoradiotherapy of non-small cell lung carcinoma (NSCLC). Intraesophageal injection of clinical-grade manganese superoxide dismutase-plasmid/liposome (SOD2-PL) 24 h prior to irradiation produced an increase in SOD2 biochemical activity in explanted esophagus. An equivalent therapeutic plasmid weight of 10 microgram ALP plasmid in the same 500 microliter of liposomes, correlated to around 52-60% of alkaline phosphatase-positive cells in the squamous layer of the esophagus at 24 h. Administration of SOD2-PL prior to irradiation mediated a significant decrease in induction of cytokine mRNA by radiation and decreased apoptosis of squamous lining cells, micro-ulceration, and esophagitis. Groups of mice receiving 35 or 37 Gy esophageal irradiation by a technique protecting the lungs and treating only the central mediastinal area were followed to assess the long-term effects of radiation. SOD2-PL-treated irradiated mice demonstrated a significant decrease in esophageal wall thickness at day 100 compared to irradiated controls. Mice with orthotopic thoracic tumors composed of 32D-v-abl cells that received intraesophageal SOD2-PL treatment showed transgenic mRNA in the esophagus at 24 h, but no detectable human SOD2 transgene mRNA in explanted tumors by nested RT-PCR. These data provide support for translation of this strategy of SOD2-PL gene therapy to studies leading to a clinical trial in fractionated irradiation to decrease the acute and chronic side effects of radiation-induced damage to the esophagus.
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PMID:Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy. 1112 Dec 10

We previously showed that vitamin A upregulated the expression of bone-type alkaline phosphatase (ALP) in fetal rat small intestine and rat intestinal IEC-6 cells. In this study, we examined interactions between retinoic acid (RA) and several growth factors/cytokines on the isozyme expression in IEC-6 cells. Epidermal growth factor and interleukins (ILs)-2, -4, -5, and -6 completely blocked the RA-mediated increase in ALP activity. In contrast, IL-1beta markedly increased the activity, protein, and mRNA of the bone-type ALP only when RA was present. IL-1beta and/or RA did not change the type 1 IL-1 receptor transcript level, whereas IL-1beta enhanced the RA-induced expressions of retinoic acid receptor-beta (RAR-beta) and retinoid X receptor-beta (RXR-beta) mRNAs and RA-mediated RXR response element binding. The synergism of IL-1beta and RA on ALP activity was completely blocked by protein kinase C (PKC) inhibitors. Our results suggest that IL-1beta may modify the ALP isozyme expression in small intestinal epithelial cells by stimulating PKC-dependent, RAR-beta- and/or RXR-beta-mediated signaling pathways.
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PMID:Interleukin-1beta enhances retinoic acid-mediated expression of bone-type alkaline phosphatase in rat IEC-6 cells. 1117 35

A 64-year-old woman with adult T cell leukemia (ATL) was admitted to our hospital with severe hypercalcemia. The serum calcium level was elevated to 14.9 mg/dl. Biochemical parameters for bone formation including serum osteocalcin (bone Gla protein, BGP) and alkaline phosphatase (ALP) were normal. The serum levels of tartrate-resistant acid phosphatase (TRAP), a parameter for bone resorption, were increased (4.6 KAU). The serum level of parathyroid hormone-related protein (PTHrP) was elevated (343 pmol/l). The cytokines with stimulatory effects on bone resorption, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha, were not detected. Serum Ca levels, PTHrP levels, and TRAP levels decreased with the decrease in ATL cells after chemotherapy, while serum BGP levels and ALP levels increased. On the 29th hospital day, ATL cells began to increase again. Then serum PTHrP levels, Ca levels, and TRAP levels increased, while serum BGP levels and ALP levels decreased. A marked excessive bone resorption with suppressed bone formation (uncoupling) occurred in this patient. The ATL cells produced not only PTHrP but also IL-1alpha and IL-1beta. These results suggest that PTHrP may act as a humoral factor and IL-1 may act as a local factor in bone metabolism of ATL patients.
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PMID:Bone resorption associated with uncoupling of osteoclastic and osteoblastic activities in adult T cell leukemia with hypercalcemia: case report. 1152 70

Oestrogen deficiency enhances bone osteoclastogenesis and bone resorption. Evidence of cooperation between stromal cells and osteoclast precursors in mice suggests that oestradiol acts by regulating cytokine release from stromal cells. Bone marrow stroma contains multipotent progenitors that give rise to many mesenchymal lineages, including osteoblasts that may regulate osteoclast differentiation. We immortalized and characterized six human bone marrow stromal cell lines (presence of Stro1, secretion of alkaline phosphatase, osteocalcin, formation of lipid droplets, and presence of alpha and beta oestrogen receptors). The response of cytokines to oestradiol was then evaluated in vitro, as were the phorbol myristate acetate (PMA)-stimulated cytokine levels. Cells had the characteristics of undifferentiated stromal cells (Stro1+, RANK-L+), and expressed alpha-oestrogen receptors. The osteoblast phenotype (amounts of alkaline phosphatase and osteocalcin) was weak and there was a poor capacity to differentiate into adipocytes. These cell lines did not respond to oestradiol by producing interleukin 6 (IL-6), IL-1 or tumour necrosis factor alpha (TNF-alpha) either constitutively or after stimulation with PMA. Moreover, RANK-L and osteoprotegerin expressions were not regulated by oestradiol in vitro. Thus, modulation of these cytokines by stromal cells do not appear to be the mechanism by which oestradiol regulates bone resorption in humans.
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PMID:Effect of oestradiol on cytokine production in immortalized human marrow stromal cell lines. 1179 22

Chronic crystal-associated arthropathies such as gout and pseudogout can lead to local bone destruction. Because osteoblasts, which orchestrate bone remodeling via soluble factors and cell-to-cell interactions, have been described in contact with microcrystals, particularly in uratic foci of gout, we hypothesized that microcrystals of monosodium urate monohydrate (MSUM) and of calcium pyrophosphate dihydrate (CPPD) could alter osteoblastic functions. MSUM and CPPD adhered to human osteoblastic cells (hOB) in vitro and were partly phagocytized as shown by scanning electron microscopy. MSUM and CPPD dose-dependently stimulated the production of PGE(2) in hOB as assessed by enzyme immunoassay, a response that was synergistically enhanced in the presence of IL-1. The mechanism of this synergism was, at least in part, at the level of the expression of cyclooxygenase-2 as evaluated by immunoblot analysis. MSUM and CPPD also stimulated the expression of IL-6 and IL-8 and reduced the 1,25-dihydroxyvitamin D(3)-induced activity of alkaline phosphatase and osteocalcin in hOB (with no synergism with IL-1). MSUM- or CPPD-stimulated expression of IL-6 in hOB pretreated with the selective cyclooxygenase-2 inhibitor NS-398 was increased, unlike that induced by IL-1 alone which was partially reduced. MSUM-, CPPD- or IL-1-induced expression of IL-8 was unchanged by pretreating hOB with NS-398. These results suggest that inflammatory microcrystals alter the normal phenotype of hOB, redirecting them toward reduced bone formation and amplified osteoblast-mediated bone resorption, abnormalities that could play a role in the bone destruction associated with chronic crystal-induced arthritis.
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PMID:Inflammatory microcrystals alter the functional phenotype of human osteoblast-like cells in vitro: synergism with IL-1 to overexpress cyclooxygenase-2. 1199 89

Myelomatous bone disease affects about 90% patients with multiple myeloma and solitary myeloma as well. In initial stage it is manifested as osteopenia with osteoporosis or osteolytic foci, pathologic fractures followed by neurologic complications. Ethiopathogenitically a role is played by cytokine interactions with local chemokines produced by myeloma cells and activated stromal and hemopoietic cells (osteoblasts, monocytes, macrophages) resp. From the TNF-alpha family glycoprotein complexes are liberated (RANK-L), which support activation and proliferation or are inhibitory (osteoprotegerins). Similarly in the family TGF-beta several izotypes of antiinflammatory cytokines are known (the most important is TGF-beta 1 and the morphogenetic protein-2), which have a fibrotizing effect in bones, because the produced osteoid is insufficiently mineralized. The effect is a pathologic remodelation of the skeleton. In the diagnosis of multiple myeloma the immunological knowledge is used in the initial diagnosis (immunophenotypization, follow up of TNF-alpha, TGF-beta 1, IL-1, IL-6 etc). Important are also biochemistry values of increased osteoresorption (changes of calcium, parathormone, excretion of collagen fission products, osteocalcin, the bone alkaline phosphatase). In the following part the authors inform about favourable results of long-term treatment with bisphosphonates (Bonefos, Ibandronate) in combination with anti-tumor chemotherapy in 364 patients. During a 15 years observation period median survival of 94 months with a 35% probability of 10 year survival was achieved with a significant decrease of bone complications in 58% compared to 14% in the placebo group.
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PMID:[Bone changes in multiple myeloma--current etiopathogenic, diagnostic and therapeutic aspects]. 1219 8


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