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)

The bone marrow stroma consists of a heterogeneous population of cells which participate in osteogenic, adipogenic, and hematopoietic events. The murine stromal cell line, BMS2, exhibits the adipocytic and osteoblastic phenotypes in vitro. BMS2 differentiation was examined in response to cytokines which share the gp130 signal transducing protein within their receptor complex. Four of the cytokines (interleukin 6, interleukin 11, leukemia inhibitory factor, and oncostatin M) inhibited hydrocortisone-induced adipocyte differentiation in a dose dependent manner based on lipid accumulation and lipoprotein lipase enzyme activity. Inhibition occurred only when the cytokines were present during the initial 24 h of the induction period; after 48 h their effects were diminished. Likewise, these cytokines increased alkaline phosphatase enzyme activity twofold in preadipocyte BMS2 cells. Both leukemia inhibitory factor and oncostatin M induced early active gene expression in resting preadipocyte BMS2 cells and decreased the steady state mRNA level of a unique osteoblastic gene marker, osteocalcin. A fifth cytokine whose receptor complex shares the gp130 protein, ciliary neurotrophic factor, did not significantly regulate stromal cell differentiation when added by itself. However, with the addition of a missing component of its receptor complex, ciliary neurotrophic factor receptor alpha protein, this cytokine also inhibited BMS2 adipogenesis. Together, these data indicate that the cytokines whose receptors share the gp130 protein can modulate stromal cell commitment to the adipocyte and osteoblast differentiation pathways.
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PMID:Regulation of bone marrow stromal cell differentiation by cytokines whose receptors share the gp130 protein. 812 83

The effects of interleukin-11(IL-11) on the differentiation of osteoblast precursors was tested using a bone nodule forming assay in rat calvaria cell cultures. IL-11 caused a dose dependent inhibition of nodule formation, with 500 U/ml IL-11 resulting in complete inhibition of nodule formation. IL-11 also caused a reduction in alkaline phosphatase expression in these cultures. These effects are similar to, but more potent than, the actions of IL-6 on these cells. These results indicate that IL-11 is an osteotropic cytokine and suggest that IL-11 may be an important inhibitor of bone formation in health and disease.
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PMID:Interleukin-11 inhibits bone formation in vitro. 828 26

A novel long-term cultured interleukin (IL)-3-dependent human myelodysplastic cell line, MDS92, was shown to contain several myeloid-lineage cells such as neutrophils, macrophages, eosinophils, and a small number of megakaryocyte-lineage cells. Therefore this cell line possesses at least bipotential characteristics of myeloid- and megakaryocyte-lineages. Granulocyte colony-stimulating factor clearly promoted the neutrophil alkaline phosphatase activity of MDS92 cells. To the contrary, the incidence and growth of CD41-positive cells were hardly affected by the addition of IL-6, IL-11, c-mpl ligand (thrombopoietin, TPO) or erythropoietin. TPO slightly supported the growth of CD34-positive cell fraction, but not CD41-positive cell fraction of MDS92 cells in combination with IL-3 or Steel factor. This cell line will be a useful tool for the study of MDS stem cells, but the mechanism of commitment of differentiation in MDS stem cells remains unknown.
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PMID:A novel factor-dependent human myelodysplastic cell line, MDS92, contains haemopoietic cells of several lineages. 854 20

Osteoclasts (OCs), which form by fusion of hematopoietic precursor cells, are typically present in large numbers in giant cell tumors of bone (GCTBs). These tumors may, therefore, contain cells which secrete factors that stimulate recruitment and differentiation of OC precursors. Multinucleated cells resembling OCs also form in cultures of human cord blood monocytes (CBMs) stimulated by 1.25 dihydroxyvitamin D3, but these cells lack the ability to form bone resorption pits, the defining functional characteristic of mature OCs. CBMs may thus require additional stimulation to form OCs; we therefore investigated whether GCTBs are a source of such a stimulus. CBMs were stimulated in long term (21 day) culture by medium conditioned by explants of GCTBs; media collected within 15 days of explant (early-CM) and after 15 days (late-CM) were employed. We also cocultured CBMs with primary GCTB-derived stromal cells as well as immortalized bone marrow stroma-derived cells. CBMs stimulated by early-CM formed resorption pits on cortical bone slices; however, stimulation by late-CM resulted in virtually no resorption. Both early-CM and late-CM increased CBM proliferation, but not the proportion of vitronectin receptor positive or multinucleated cells. Coculture of CBMs with stromal cells of GCTBs or bone marrow did not result in bone resorption, although these stromal cells (most expressing alkaline phosphatase but progressively losing parathyroid hormone receptor expression) expressed mRNA for cytokines involved in OC differentiation, including macrophage-CSF, granulocyte-macrophage-CSF, IL-11, IL-6, and stem cell factor. Our results indicate that CBMs are capable of terminal OC differentiation in vitro, a process requiring 1,25 dihydroxyvitamin D3 as well as diffusible factor(s) which can be derived from GCTB. Stromal cells of GCTB may produce such factors in vivo, but do not support OC differentiation in vitro, possibly through phenotypic instability in culture.
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PMID:Human cord blood monocytes undergo terminal osteoclast differentiation in vitro in the presence of culture medium conditioned by giant cell tumor of bone. 881 3

Interleukin (IL)-6, IL-11, leukemia inhibitory factor, and oncostatin M similarly induce osteoclast formation in cocultures of osteoblastic cells and bone marrow cells. These cytokines share a common signal transducer, gp130, which forms a receptor complex with the specific receptor for each cytokine. To investigate the role of gp130 in osteoclast development, we examined bone tissues in gp130-deficient and wild-type newborn mice of the ICR background. Soft x-ray radiographs and microfocus x-ray computed tomographs revealed that bone marrow cavities were present in tibiae and radii of both wild-type and gp130-deficient mice. Microfocus x-ray computed tomography and histological examination demonstrated a decrease in the amount of trabeculae at the metaphysial region in tibiae and radii of the gp130-deficient mice compared with the wild-type mice. The number ofosteoclasts in gp130-deficient mice was about double that in the wild-type mice. There were no apparent differences in the distributions of alkaline phosphatase-positive osteoblasts and the osteoid surface on the trabecular bone at the metaphysial region between the wild-type and gp130-deficient mice. The volume of mineralized trabecular bones was also decreased at mandibulae, accompanied by the increased number of osteoclasts in gp130-deficient mice compared with the wild-type and heterozygous mice. These results suggest that the formation of osteoclasts is not solely dependent on gp130 signaling, at least during fetal development. The osteoclastic bone resorption in gp130-deficient mice may be caused by the functional redundancy of bone-resorbing hormones and cytokines other than those of the IL-6 family.
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PMID:Osteoclasts are present in gp130-deficient mice. 934 27

The chronic inflammatory response to abrasion particles from total hip replacement (THR) is believed to cause osteolysis and to contribute to prosthetic loosening. The expression of interleukin-11(IL-11) and its major cellular sources in the interface and pseudocapsular tissues obtained from total hip revisions performed for aseptic loosening were investigated. The avidin-biotin-peroxidase complex (ABC) and alkaline phosphatase-anti-alkaline phosphatase (APAAP) methods were used for staining and VIDAS image analysis for quantification. IL-11 was found in the interface and pseudocapsular tissues in the aseptic loosening of THR. IL-11 containing cells were more numerous in the interface (760 +/- 171 cells) and pseudocapsular tissues (684 +/- 171 cells) than in the control synovial tissue (235 +/- 68 cells). Because IL-11 is an important component of cytokine network mediating osteoblast-osteoclast communication in normal and pathological bone remodeling, the current findings suggest that IL-11 may contribute to periprosthetic osteolysis and to the loosening of THR.
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PMID:Interleukin-11 (IL-11) in aseptic loosening of total hip replacement (THR). 980

Cytokines that transduce their signals either through glycoprotein 130 (gp130) homodimers or gp 130/leukemia inhibitory factor (LIF) receptor beta heterodimers are potent inducers of osteoclast development in vitro as well as in vivo; and interleukin (IL)-6 has been recognized as an important pathogenic factor in diseases characterized by increased bone remodeling, such as the osteoporosis of sex steroid deficiency. Based on evidence that the same cytokines can also promote committed osteoblast differentiation and stimulate bone formation in vitro and in vivo and that mesenchymal cell differentiation toward the osteoblast lineage may be a prerequisite for osteoclastogenesis, we have investigated whether gp130 activation can affect the differentiation of uncommitted mesenchymal progenitors. Using as our model murine embryonic fibroblasts (EF), we found that IL-6 or IL-11 in combination with their soluble receptors (sIL-6R or sIL-11R) increased dose-dependently the number of alkaline phosphatase (AP)-positive cells in 3-6-day-long cultures. Moreover, EF cells maintained with IL-6/sIL-6R in the presence of ascorbic acid and beta-glycerophosphate expressed osteocalcin messenger RNA (mRNA) by 2 weeks and formed a matrix containing mineralized collagen fibers by 3 weeks. This prodifferentiation effect was specific for the osteoblastic lineage, as we found no evidence for increased differentiation of chondrocytes, adipocytes, or muscle cells. Unlike IL-6/sIL-6R, LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) did not promote osteoblastic differentiation of EF cells. This pattern of specificity was accounted for by the finding that EF cells express gp130, but not the ligand-binding subunit of the IL-6 receptor (gp80) nor the LIF receptor beta. These observations add credence to the contention that increased production of gp130-utilizing cytokines and their receptors in pathological conditions like sex steroid deficiency is indeed responsible for not only the increased osteoclastogenesis, but also the increased osteoblastogenesis, and thereby for the increased rate of bone remodeling.
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PMID:Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. 982 38

Overproduction of thyroid hormones promotes bone resorption in vivo and in vitro, and we have evaluated whether mediators of such effects could include the osteotropic cytokines. Previous studies have demonstrated raised serum interleukin (IL)-6 in thyrotoxic patients, but differentiating the contribution of the elevated thyroid hormones from that of the autoimmune inflammation present in Graves' disease (GD) has been difficult. We undertook a longitudinal study of 34 patients (19-45 yr old) with GD, toxic nodular goiter (TNG), or a history of thyroid carcinoma but no evidence of disease recurrence, receiving sufficient T4 to suppress TSH. Controls were 12 euthyroid females. The following measurements were made basally and for 6 months after carbimazole treatment: serum free T4, T3, bone-specific alkaline phosphatase (b-ALP), IL-6, IL-8, IL-1beta, tumor necrosis factor-alpha, IL-11, and urinary deoxypyridinoline (Udpd). Compared with controls (IL-6, 1.1 +/- 0.3 ng/L; IL-8, 3.2 +/- 0.8 ng/L), untreated patients with GD and TNG had elevated IL-6 (GD, 7.11 +/- 0.88 ng/L; TNG, 7.30 +/- 0.77 ng/L; P < 0.001) and IL-8 (GD, 10.3 +/- 1.23 ng/L; TNG, 9.81 +/- 1.27 ng/L; P < 0.001). These levels fell after treatment and were then indistinguishable from those in control subjects. Thyroid carcinoma patients on TSH suppressive therapy also had significantly raised levels of IL-6 (2.5 +/- 0.42 ng/L) and IL-8 (4.4 +/- 0.63 ng/L). When data from all the patients were pooled, the levels of IL-6 and IL-8 correlated with serum T3 and free T4 but not with Udpd or b-ALP. IL-1beta, IL-11, and tumor necrosis factor-alpha were not raised in any patient. The elevations in serum IL-6 and -8 that occur in hyperthyroidism seem to result from the chronic effects of thyroid hormone excess rather than the accompanying autoimmune inflammatory condition produced by Graves' thyroid or eye disease. The site of the presumed increased production of IL-6 and -8 is most likely from bone osteoblasts, despite the inability of bone markers (such as Udpd and b-ALP) to correlate with acute changes in thyroid hormone status produced by antithyroid therapy.
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PMID:Serum cytokines in thyrotoxicosis. 1002 97

Thiazide diuretics have been shown to decrease bone loss and improve bone mineral density, while long-term furosemide therapy has been suggested to decrease bone mineral content. However, the direct effects of these diuretics on osteoblastic cells are not well established. Some investigators have reported direct effects of thiazides on osteoblastic cells but the results remain controversial, and there are few data about the direct effect of furosemide on osteoblastic cells. We investigated the effects of hydrochlorothiazide (HCTZ) and furosemide on proliferation, alkaline phosphatase activity, osteocalcin, and interleukin-6/interleukin-11 (IL-6/IL-11) secretion in cultured normal human bone marrow stromal osteoprogenitor cells (hBMSCs). Treatment with HCTZ or furosemide for 24 hours in the concentration range of 10(-6) to 10(-4) mol/L did not affect 3H-thymidine incorporation in hBMSCs. Cellular alkaline phosphatase activity and osteocalcin production were not changed significantly by treatment with HCTZ or furosemide (up to 10(-4) mol/L) during culture. There was also no significant difference in IL-6 and IL-11 production in hBMSCs. These results suggested that HCTZ or furosemide had no significant direct effect on proliferation, alkaline phosphatase activity, osteocalcin, and IL-6/IL-11 production in hBMSCs, and the effects of these diuretics on bone mass may be related to the indirect action on calcium balance.
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PMID:Effects of hydrochlorothiazide and furosemide diuretics on human bone marrow stromal osteoprogenitor cells. 1064 59

Although osteoblasts have been shown to respond to estrogens and express both isoforms of the estrogen receptor (ER alpha and ER beta), the role each isoform plays in osteoblast cell function and differentiation is unknown. The two ER isoforms are known to differentially regulate estrogen-inducible promoter-reporter gene constructs, but their individual effects on endogenous gene expression in osteoblasts have not been reported. We compared the effects of 17 beta-estradiol (E) and tamoxifen (TAM) on gene expression and matrix formation during the differentiation of human osteoblast cell lines stably expressing either ER alpha (hFOB/ER alpha 9) or ER beta (hFOB/ER beta 6). Expression of the appropriate ER isoform in these cells was confirmed by northern and western blotting and the responses to E in the hFOB/ER beta 6 line were abolished by an ER beta-specific inhibitor. The data demonstrate that (1) in both the hFOB/ER cell lines, certain responses to E or TAM (including alkaline phosphatase, IL-6 and IL-11 production) are more pronounced at the late mineralization stage of differentiation compared to earlier stages, (2) E exerted a greater regulation of bone nodule formation and matrix protein/cytokine production in the ER alpha cells than in ER beta cells, and (3) the regulated expression of select genes differed between the ER alpha and ER beta cells. TAM had no effect on nodule formation in either cell line and was a less potent regulator of gene/protein expression than E. Thus, both the ER isoform and the stage of differentiation appear to influence the response of osteoblast cells to E and TAM.
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PMID:Estrogen regulation of human osteoblast function is determined by the stage of differentiation and the estrogen receptor isoform. 1159 13


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