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)

Granulocyte colony-stimulating factor (G-CSF) has been shown to affect the biochemical markers of bone metabolism, including serum bone alkaline phosphatase (BALP), serum osteocalcin, and urine deoxypyridinoline. To determine the association between bone resorption and formation and the G-CSF-induced mobilization of peripheral blood stem cells (PBSC), we examined these markers during mobilization in 19 healthy donors. The average (+/- SEM) serum BALP level before treatment was 81.6 +/- 17.0 IU/dL, and the level increased significantly to 117.7 +/- 15.8 IU/dL on day 5 of G-CSF administration (P < .0001). The urine deoxypyridinoline level before treatment was 12.3 +/- 2.4 nmol/mmol creatinine, and this level also increased significantly to 19.4 +/- 3.0 nmol/mmol creatinine on day 5 of G-CSF administration (P < .0001). In contrast, the average level of serum osteocalcin significantly decreased from 8.07 +/- 2.88 ng/mL to 1.53 +/- 0.18 ng/mL on day 5 (P = .0353). During G-CSF administration, we also studied the serum levels of various cytokines (IL-1beta, osteoclastogenesis inhibitory factor [OCIF], IL-6, tumor necrosis factor alpha, transforming growth factor beta, interferon-gamma, macrophage colony-stimulating factor) related to bone metabolism. Only the kinetics of OCIF were significantly affected. The serum level of OCIF increased immediately after the start of G-CSF administration and remained high during G-CSF administration. These results demonstrate that high-dose G-CSF affects bone metabolism and that OCIF may play a role in bone metabolism. Consistent with the notion that G-CSF affects bone metabolism, a significant correlation was observed between CD34+ cell yield and the increase in urine deoxypyridinoline but not for the changes in serum BALP and osteocalcin levels. This result suggests that bone resorption is either directly or indirectly related to the mobilization of PBSC by G-CSF.
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PMID:Effect of granulocyte colony-stimulating factor on bone metabolism during peripheral blood stem cell mobilization. 1256 3

We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD+, to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. Its activation in the osteoclast triggers Ca2+ release through ryanodine receptors (RyRs), stimulation of interleukin-6 (IL-6), and an inhibition of bone resorption. Here, we have examined the consequences of deleting the CD38 gene in mice on skeletal remodeling. We report that CD38-/- mice displayed a markedly reduced bone mineral density (BMD) at the femur, tibia, and lumbar spine at 3 months and at the lumbar spine at 4 months, with full normalization of the BMD at all sites at 5 months. The osteoporosis at 3 months was accompanied by a reduction in primary spongiosa and increased osteoclast surfaces on histomorphometric analysis. Hematopoetic stem cells isolated ex vivo from CD38-/- mice showed a dramatic approximately fourfold increase in osteoclast formation in response to incubation for 6 days with RANK-L and M-CSF. The osteoclasts so formed in these cultures showed a approximately 2.5-fold increase in resorptive activity compared with wild-type cells. However, when adherent bone marrow stromal cells were allowed to mature into alkaline phosphatase-positive colony-forming units (CFU-Fs), those derived from CD38-/- mice showed a significant reduction in differentiation compared with wild-type cells. Real-time RT-PCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, alpha, beta, and gamma. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions as a cellular NAD+ "sensor," particularly during periods of active motility and secretion.
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PMID:Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption. 1263 76

Estrogens have complex effects on the skeleton, including regulation of modeling and maintenance of bone mass, which vary with cell type and developmental stage. Osteoblasts are key regulators of skeletal matrix synthesis and degradation. However, whether osteocytes, osteoblasts or earlier progenitors mediate estrogen effects, and the importance of estrogen receptors (ERs) alpha and beta, remain unclear. To address estrogen response in human cells closely related to secretory osteoblasts, we studied MG63 cells with ERalpha or ERbeta reduced to low levels by stable transfection of antisense plasmids. Collagen and alkaline phosphatase expression increased with estrogen in wild-type and ERalpha-suppressed cells, but not in ERbeta-suppressed cells. Matrix secretion occurs as osteoblasts cease dividing, and, in keeping with this, cell proliferation was reduced by estrogen except in ERbeta-antisense cells. No effects of estrogen on wild type or ER-suppressed cells were seen in expression of BMP 2, the BMP antagonist noggin, or Indian hedgehog, products that regulate differentiation of osteoblasts. In contrast to expectations that estrogen would modulate bone degradation, RANKL, CSF-1, and osteoprotegerin did not respond measurably to estrogen, regardless of ER status. In keeping with this result, estrogen response was not observed in assays of osteoclast development from CD14 cells supported by wild-type or ER-silenced MG63 cells. Since estrogens are major regulators of bone degradation in vivo, estrogen effects on osteoclasts may depend on interaction with stimuli present in bone but absent in the model studied. cDNA hybridization showed that additional estrogen-binding proteins including ERRalpha and BCAR3 were expressed by MG63, but estrogen effects in ERbeta-silenced cells were small, so these proteins are either minor regulators in MG63 cells, or act in concert with stimuli in addition to estrogen. We conclude that, in the MG63 cell line, estrogen increases synthesis of matrix proteins via ERbeta, and that, in the absence of additional stimuli, these cells are not major mediators of estrogen effects on osteoclast differentiation. Further, ERalpha is probably much more important in earlier stages of skeletal development, such as growth plate response, than in osteoblasts.
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PMID:Estrogen receptor-beta modulates synthesis of bone matrix proteins in human osteoblast-like MG63 cells. 1268 16

Apolipoprotein E (apo E) has an impact on lipid metabolism and its production by macrophages is considered to play a protective role against atherosclerosis. Apo A-I stimulates secretion of apo E from macrophages. We developed a new method to evaluate the ability of human monocyte-derived macrophages to secrete apo E, and the effects of factors such as apo A-I were examined. Monocytes separated from peripheral venous blood were cultured. The levels of apo E in macrophage-conditioned medium were quantified by immunoblotting with an anti-human apo E antiserum conjugated with alkaline phosphatase. The basal levels of apo E secretion and the response to exogenous apo A-I in macrophages from 10 healthy volunteers were measured. Sufficient accuracy and sensitivity were confirmed and coefficient of variation of the method was 18 +/- 11% (n = 10). It was confirmed that macrophage secreted apo E in a concentration-dependent manner in response to M-CSF and apo A-I. The average apo E concentration in the conditioned medium of macrophages from 10 healthy subjects was 30.9 +/- 14.7 ng/mg cell protein. After the addition of apo A-I, the average apo E concentration increased, by about 60%, to 49.4 +/- 29.7 ng/mg cell protein (p < 0.05). There was a positive correlation between the apo A-I-induced increase and plasma LDL cholesterol levels (r = +0.54, p < 0.05).
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PMID:Quantitative analysis of apolipoprotein E secretion by human monocyte-derived macrophages in culture. 1460 60

While it has been assumed that osteoblasts in the human support osteoclast formation, in vitro evidence of this is currently lacking. We tested the ability of normal human trabecular bone-derived osteoblasts (NHBCs) to support osteoclast formation from human peripheral blood mononuclear cells (PBMC) in response to treatment with either 1alpha,25-dihydroxyvitamin D3 (1,25D) or parathyroid hormone (PTH), using a serum-replete medium previously used to support human osteoclast formation on a stroma of murine ST-2 cells. Under these conditions, NHBC did not support osteoclast formation, as assessed by morphological, histochemical, and functional criteria, despite our previous results demonstrating a link between induction of RANKL mRNA expression and NHBC phenotype in these media. We next tested a defined, serum-free medium (SDM) on NHBC phenotype, their expression of RANKL and OPG, and their ability to support osteoclast formation. SDM, containing dexamethasone (DEX) and 1,25D, induced phenotypic maturation of NHBC, based on the expression of STRO-1 and the bone/liver/kidney isoform of alkaline phosphatase (AP). PTH as a single factor did not induce phenotypic change. 1,25D and DEX induced the greatest ratio of RANKL:OPG mRNA, predictive of supporting osteoclast formation. Consistent with this, co-culture of NHBC with CD14+ PBMC, or bone marrow mononuclear cell (BMMC), or CD34+ BMMC precursors in SDM + 1,25D + DEX, resulted in functional osteoclast formation. Osteoclast formation also occurred in PTH + DEX stimulated co-cultures. Interestingly, SDM supplemented with recombinant RANKL (25-100 ng/ml) and M-CSF (25 ng/ml), did not induce osteoclast formation from any of the osteoclast precursor populations in stromal-free cultures, unlike serum-replete medium. This study demonstrates that under the appropriate conditions, adult human primary osteoblasts can support de novo osteoclast formation, and this model will enable the detailed study of the role of both cell types in this process.
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PMID:Human trabecular bone-derived osteoblasts support human osteoclast formation in vitro in a defined, serum-free medium. 1557 98

It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and in clinical studies. However, the mechanism by which US achieves these outcomes is not clear. Here we investigated the effect of US stimulation on the differentiation of osteoblasts and osteoclastogenesis. The effect of different intensities of US stimulation (1 MHz, continuous wave) on the osteoblastic cell line MC3T3-E1 or primary cultured osteoblasts was examined. Flow cytometry showed that US stimulation at 125 mW/cm2 for 10 min transiently increased the surface expression of alpha2, alpha5, and beta1 integrins in both MC3T3-E1 and primary osteoblasts. Fluorocytochemistry showed that the actin cytoskeleton also reorganized in response to US stimulation. When the MC3T3-E1 cells were cultured in differentiation medium containing vitamin C and beta-glycerophosphate, long-term US stimulation (10 min/day for 11 days) increased mineralized nodule formation, collagen content, and alkaline phosphatase activity. The intensity at 125 mW/cm2 exerts the most prominent action. Effect of long-term US stimulation on the osteoclastogenesis was also examined. US stimulation at a power of 62.5 or 125 mW/cm2 markedly inhibited RANKL plus M-CSF-induced osteoclastic differentiation from bone marrow stromal cells. These findings suggest that US has a regulatory effect on the integrin expression and the differentiation of osteoblasts and osteoclastogenesis, which may contribute to the beneficial effects of US on the fracture repair.
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PMID:Regulation by ultrasound treatment on the integrin expression and differentiation of osteoblasts. 1578 Sep 53

Adiponectin, an adipose-derived hormone, exhibits various biological functions, such as increasing insulin sensitivity, protecting hypertension, and suppression of atherosclerosis, liver fibrosis, and tumor growth. Here, we report the role of adiponectin on bone metabolism. C57BL/6J mice were treated with adenovirus expressing lacZ or adiponectin, and their bones were analyzed by three-dimensional microcomputed tomography. Adiponectin-adenovirus treatment increased trabecular bone mass, accompanied by decreased number of osteoclasts and levels of plasma NTx, a bone-resorption marker. In vitro studies showed that adiponectin inhibited M-CSF- and RANKL-induced differentiation of mouse bone marrow macrophages and human CD14-positive mononuclear cells into osteoclasts and also suppressed the bone-resorption activity of osteoclasts. Furthermore, adiponectin enhanced mRNA expression of alkaline phosphatase and mineralization activity of MC3T3-E1 osteoblasts. Our results indicate that adiponectin exerts an activity to increase bone mass by suppressing osteoclastogenesis and by activating osteoblastogenesis, suggesting that adiponectin manipulation could be therapeutically beneficial for patients with osteopenia.
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PMID:Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. 1585 Jul 90

When human blood monocytes were cocultured with stromal cells derived from human giant cell tumor of bone (GCTSC) and a Millipore filter (0.4 microm) was interposed between monocytes and GCTSC, multinucleated giant cell formation of monocytes was induced. The multinucleated giant cells have characters as osteoclast-like cells, indicating that a soluble osteoclast-inducing factor(s) is secreted from GCTSC expressing RANK, RANKL/ODF/OPGL and TACE mRNA. Furthermore, OCIF/OPG inhibited GCTSC-induced osteoclastogenesis, showing that the RANK-RANKL system is involved in GCTSC-induced osteoclastogenesis and that soluble form of ODF/RANKL induces osteoclasts from monocytes. GCTSC expressed the cytokine mRNAs such as M-CSF, GM-CSF, IL-3, IL-4, IL-6, and IFN-gamma mRNAs. None of IL-1ralpha, IL-1alpha, IL-1beta, IL-2, IL-4, IL-10, IL-18, TNF-alpha, G-CSF and IFN-gamma could be detected in all culture media. A significant amount of IL-6 could be detected in the culture media of all GCTSC. IL-8 was found in the culture media of two GCTSC and two osteosarcoma-derived cells. M-CSF was detected in all culture media. GCTSC express CaSR, and stimulation of GCTSC with either extracellular Ca(2+) or neomycin, agonist of CaSR, augmented the expression of RANKL. Some lines of GCTSC expressed alkaline phosphatase, osteocalcin and Cbfa1, suggesting that GCTSC are intimately related to osteoblastic lineage.
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PMID:Cytological properties of stromal cells derived from giant cell tumor of bone (GCTSC) which can induce osteoclast formation of human blood monocytes without cell to cell contact. 1602 7

Osteopetrotic (op/op) mice fail to exhibit bone remodeling because of a defective osteoclast formation due to a lack of macrophage colony-stimulating factor. In this study, we investigated the femora of op/op mice to clarify whether the osteoblastic population and bone mineralization are involved in osteoclasts or their bone resorption. The op/op mice extended the meshwork of trabecular bones from the chondro-osseous junction to the diaphyseal region. In the femoral metaphyses of op/op mice, intense alkaline phosphatase (ALPase)-positive osteoblasts were observed on the metaphyseal bone in close proximity to the erosion zone of the growth plates. Von Kossa's staining revealed scattered mineralized nodules and a fine meshwork of mineralized bone matrices while the wild-type littermates developed well-mineralized trabeculae parallel to the longitudinal axis. In contrast to the metaphysis, some op/op diaphyses showed flattened osteoblasts with weak ALPase-positivity, and the other diaphyses displayed bone surfaces without a covering by osteoblasts. It is likely, therefore, that the osteoblastic population and activity were lessened in the op/op diaphyses. Despite the osteopetrotic model, von Kossa's staining demonstrated patchy unmineralized areas in the op/op diaphyses, indicating that a lower population and/or the activity of osteoblasts resulted in defective mineralization in the bone. Transmission electron microscopy disclosed few osteoblasts on the diaphyseal bones, and instead, bone marrow cells and vascular endothelial cells were often attached to the unmineralized bone. Osteocytes were embedded in the unmineralized bone matrix. Thus, osteoclasts appear to be involved in the osteoblastic population and activity as well as subsequent bone mineralization.
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PMID:Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice. 1618 47

We show that sulforaphane inhibits osteoclastogenesis in the presence of macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor-kB ligand (RANKL) in osteoclast (OC) precursors. Sulforaphane, an aliphatic isothiocyanate, is a known cancer chemo-preventative agent with anti-oxidative properties. Nuclear factor-kB (NF-kB) is a critical transcription factor in RANKL-induced osteoclastogenesis, and electrophoretic mobility shift assays (EMSAs) and assay of NF-kB-mediated secreted alkaline phosphatase (SEAP) revealed that sulforaphane selectively inhibited NF-kappaB activation induced by RANKL. Inhibition may involve interaction of sulforaphane with thiol groups, since it was prevented by reducing agents.
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PMID:Sulforaphane inhibits osteoclastogenesis by inhibiting nuclear factor-kappaB. 1640 51


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