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)

Endochondral bone formation induced by bone morphogenetic protein (BMP) involves expression of collagen Types I and II and alkaline phosphatase (ALP) genes. Expression of these genes was studied in mice after implantation of BMP. The amount of Type I collagen mRNA increased from Day 3 to Day 7, when mesenchymal cell aggregation was observed. On Day 17, Type I collagen mRNA expression was correlated with an increased number of osteoblasts. Type II collagen mRNA increased from Day 7 and coincided with chondroblast appearance. This increase was suppressed by Day 17, although hypertrophic and degenerative chondrocytes were present. Alkaline phosphatase mRNA increased markedly from Day 7 with the appearance of chondroblasts. The high level of ALP mRNA continued until Day 11, during chondrogenesis. Mineral deposition was first observed roentgenographically on Day 11. Thus, BMP-induced bone formation occurs with the expression of collagen Types I and II and ALP genes.
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PMID:Collagen and alkaline phosphatase gene expression during bone morphogenetic protein (BMP)-induced cartilage and bone differentiation. 851 29

Osteogenic protein-1 (OP-1, BMP-7), a bone morphogenetic protein in the transforming growth factor-beta superfamily, induces endochondral bone formation in vivo, but the mechanism of action of OP-1 in osteogenesis is not yet established. Three murine clonal cell lines in different stages of differentiation exhibit graded responses to recombinant human OP-1: the mouse embryonal carcinoma ATDC5 cell, with potential for chondroblastic differentiation; the osteoblast-like MC3T3-E1 cell derived from mouse calvaria; and the multipotent fibroblastic C3H10T1/2 cell derived from mouse embryo connective tissue. We show that OP-1 acts on early stage mesenchymal progenitor cells (ATDC5, C3H10T1/2) to induce chondroblastic differentiation, while OP-1 strongly enhances the osteoblastic phenotype of committed osteoblasts (MC3T3-E1), possibly explaining its induction of the endochondral ossification cascade in vivo. Markers of osteoblastic, chondroblastic, and adipocytic differentiation are compared. OP-1 is strongly mitogenic for ATDC5, showing dose-dependent (2.5-80 ng/ml) induction of Alcian blue staining, alkaline phosphatase activity, and mRNA expression for collagen types II and IX, and matrix Gla protein. MC3T3-E1 cells do not proliferate or stain with Alcian blue in response to OP-1, but express elevated levels of alkaline phosphatase and osteocalcin. While low-dose OP-1 treatment of C3H10T1/2 induces only adipocyte-like cells filled with lipid droplets, a high dose (500 ng/ml) causes the same cells to also exhibit chondrocytic properties. Thus, OP-1 can induce differentiation along elements of the endochondral ossification pathway according to the stage and potential of the target cell.
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PMID:Human osteogenic protein-1 induces chondroblastic, osteoblastic, and/or adipocytic differentiation of clonal murine target cells. 854 71

The objectives of the present research on the osteopetrotic mouse are to investigate the factors influencing heterotopic bone development. The osteopetrotic mutant was deficient in macrophage colony stimulating factor and failed to activate functioning monocytes, macrophages, and osteoclasts. Macrophage colony stimulating factor deficiency also caused a heretofore undescribed delay in organization and absorption of hematomas resulting from surgical operations. Surgically implanted in a heterotopic site, bone morphogenetic protein induced approximately 10% more bone in osteopetrotic than littermate+/? mice. Radiographically, the heterotopic bone was at least 50% denser than new bone. The new bone was metachromatic or slightly basophilic rather than eosinophilic and undermined with large deposits of hypercalcified hypertrophic cartilage. Bone mineral in the osteopetrotic mouse was deposited in an apatite-like form with a higher calcium/phosphorus ratio than the bone of +/? littermates. High levels of alkaline phosphatase synthesis were sustained longer in the osteopetrotic mouse than in the +/? littermate. Tartrate resistant acid phosphatase synthesis was almost nil in osteopetrotic mice during the first 4 weeks, and thereafter appeared coincidental with spontaneous remission of osteopetrosis at 6 weeks. Implants of the mineralized cortical bone matrix of the osteopetrotic mouse showed minimal if any bone morphogenetic protein activity of matrix of +/? littermate or otherwise normal mice. The cause of the remission of the bone disorder in the osteopetrotic mouse is not known but is of great interest to students studying the problem of coupling of bone formation to bone resorption.
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PMID:Bone morphogenetic protein-induced heterotopic bone in osteopetrosis. 859 66

Osteogenic protein-1 (OP-1) is a member of the bone morphogenetic protein family and has been shown to induce new bone formation in vivo. In the present study, we determined whether the expression of the IGF system, a significant growth factor system in bone, was altered by OP-1 in primary cultures of fetal rat calvarial cells. Levels of messenger RNA (mRNA) encoding insulin-like growth factor I (IGF-I), IGF-II, IGF-I receptor, and IGF-binding proteins (IGFBP-1 to -6) were determined after OP-1 treatment. The level of total IGF-I mRNA was elevated in an OP-1 concentration (0-1000 ng/ml)-dependent manner, with maximal stimulation of IGF-I mRNA of 2- to 3-fold apparent 24 h after treatment. The increase in the IGF-I mRNA level involved a preferential stimulation of transcripts initiated at start site 2 in the exon 1 promoter. The level of IGF-II mRNA also increased by approximately 2-fold in OP-1 treated cells in a concentration-dependent manner. The level of IGF-I receptor mRNA was not altered by treatment. Whereas IGFBP-1 mRNA was not detected in these cells, IGFBP-2 mRNA was expressed, but the expression was not changed after treatment for 48 h in the concentration range (0-1000 ng/ml) tested. The IGFBP-3 mRNA level was increased slightly 48 h after OP-1 treatment in a concentration-dependent manner. The IGFBP-4, -5, and -6 mRNA levels decreased dramatically in an OP-1 concentration-dependent manner. In addition, coincubation of antisense oligonucleotides corresponding to IGF-I or -II mRNA sequence with OP-1 reduced the OP-1 induced elevation in alkaline phosphatase activity. The present results suggest that the differentiation of rat osteoblastic cells in response to OP-1 is mediated in part by increased IGF-I -II gene expression and alterations in the gene expression of different IGFBPs.
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PMID:Osteogenic protein-1-mediated insulin-like growth factor gene expression in primary cultures of rat osteoblastic cells. 861 32

Effects of bone morphogenetic protein (BMP)-12 and BMP-13, new members of the BMP family which belong to the transforming growth factor (TGF)-beta superfamily, on terminal differentiation of myoblasts were examined in C2C12 and L-6 myoblasts. When the myoblasts were cultured with BMP-12 or BMP-13, the expression of the myosin heavy chain and the formation of multinucleated myotubes mRNA in L-6 cells. The inhibitory effects of BMP-12 and BMP-13 on myogenic differentiation were similar to the effects of BMP-2, though their potencies were lower than BMP-2. Unlike BMP-2, neither BMP-12 nor BMP-13 induced alkaline phosphatase activity in C2C12 myoblasts. The differences in the biological activities of these new BMPs suggest that the intracellular signalling pathway used by BMP-12 and BMP-13 differs from that of BMP-2.
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PMID:Bone morphogenetic protein-12 and -13 inhibit terminal differentiation of myoblasts, but do not induce their differentiation into osteoblasts. 867 Feb 3

Growth/differentiation factor-5 (GDF-5) is a member of the bone morphogenetic protein (BMP) family, which plays an important role in bone development in vivo. Mutations in the GDF-5 gene result in brachypodism in mice and Hunter-Thompson type chondrodysplasia in human. BMPs transduce their effects through binding to two different types of serine/threonine kinase receptors, type I and type II. However, binding abilities appear to be different among the members of the BMP family. BMP-4 binds to two different type I receptors, BMP receptors type IA (BMPR-IA) and type IB (BMPR-IB), and a type II receptor, BMP receptor type II (BMPR-II). In addition to these receptors, osteogenic protein-1 (OP-1, also known as BMP-7) binds to activin type I receptor (ActR-I) as well as activin type II receptors (ActR-II and ActR-IIB). Here we investigate the binding and signaling properties of GDF-5 through type I and type II receptors. GDF-5 induced alkaline phosphatase activity in a rat osteoprogenitor-like cell line, ROB-C26. 125I-GDF-5 bound to BMPR-IB and BMPR-II but not to BMPR-IA in ROB-C26 cells and other nontransfected cell lines. Analysis using COS-1 cells transfected with the receptor cDNAs revealed that GDF-5 bound to BMPR-IB but not to the other type I receptors when expressed alone. When COS-1 cells were transfected with type II receptor cDNAs, GDF-5 bound to ActR-II, ActR-IIB, and BMPR-II but not to transforming growth factor-beta type II receptor. In the presence of type II receptors, GDF-5 bound to different sets of type I receptors, but the binding was most efficient to BMPR-IB compared with the other type I receptors. Moreover, a transcriptional activation signal was efficiently transduced by BMPR-IB in the presence of BMPR-II or ActR-II after stimulation by GDF-5. These results suggest that BMPR-IB mediates certain signals for GDF-5 after forming the heteromeric complex with BMPR-II or ActR-II.
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PMID:Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. 870 14

The purpose of this study was to investigate the effect of ovariectomy on osteoinductive activity in the bone in rat. Homograft implantation of decalcified humeral diaphysis from ovariectomized or sham-operated rats was performed and harvested after several time periods. A significant decrease in bone induction was found in terms of soft X-ray photography, alkaline phosphatase activity, mineral content and expression of osteocalcin (BGP; bone gla-protein) in the implants from the ovariectomized group in comparison to those from the sham-operated animals. This result suggested that the level of osteoinductive activity, probably due to bone morphogenetic protein, decreased in ovariectomized animals.
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PMID:Ovariectomy decreases osteogenetic activity in rat bone. 870 22

Demineralized bone powder (DBP) prepared from human cortical bone was implanted into subcutaneous pouches of athymic Nu/Nu mice for 28 days. The osteoinductive capacity was evaluated by histomorphometry of the induced cartilage and bone, and by alkaline phosphatase activity in the implant. Very small amounts of new bone and cartilage were found at histological analysis, confirming that human DBP is much less osteoinductive than that from other species. Whereas the morphometric data of the implants from the young and aged donors were not significantly different, the alkaline phosphatase activity was significantly lower in the implants from the old donors than from the younger ones. This difference between the morphometric and biochemical results could reflect the fact that the enzymatic activity is already present in the osteoprogenitor cells. At 28 days, the osteoblastic activity in contact with DBP from the aged group is characterized by a decrease in the enzymatic amount which is not yet visible at the tissue level. This tendency to a decrease in the osteoinductive capacity of bone matrix is an additional aspect of the age-related alterations which occur in bone tissue and could be attributed to modifications of different proteins of the bone matrix, including bone morphogenetic protein.
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PMID:Aging effect on inductive capacity of human demineralized bone matrix. 890 1

Bone maintenance requires a continuous source of osteoblasts throughout life. Its remodeling and regeneration during fracture repair is ensured by osteoprogenitor stem cells which are part of the stroma of the bone marrow (BM). Many investigators have reported that in cultured BM stromal cells there is a cell population that will differentiate along an osteogenic lineage if stimulated by the addition of osteogenic inducers, such as dexamethasone (dex), beta-glycerophosphate (beta-GP), transforming growth factor beta-1 (TGF-beta 1) and bone morphogenetic protein-2 (BMP-2). Here we report the effects of demineralized bone matrix (DBM) on the osteogenic differentiation of BM stromal cells in vitro, using morphological criteria, alkaline phosphatase (AP) activity, and calcium accumulation. DBM and DBM-conditioned medium (DBMcm) enhanced bone formation in the presence of dex and beta-GP, whereas DBM particles caused changes in the cell phenotype. Temporal expression of total and skeletal AP by BM stromal cells from 4-week-old rats showed a biphasic pattern enhanced by DBM and suggesting the presence of two cell populations. In one population, AP synthesis reaches a maximum during the first week in culture, following which cells either die or loose their ability to synthesize AP. A second, less abundant population begins to proliferate and synthesize AP during the second and third weeks. The synthesis of AP, which often decreases by the third week, can be maintained at high levels only if DBM is added to the cultures. BM stromal cells isolated from 24- and 48-week-old rats showed a decrease or loss of this biphasic AP expression pattern compared with cells isolated from 4-week-old rats. The addition of DBM to cultures derived from 24- and 48-week-old rats stimulated mostly the second cell population to synthesize AP, suggesting that DBM contains a factor(s) that acts on a specific bone marrow cell population by increasing the proliferation of active cells or inducing the differentiation of dormant cells.
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PMID:Demineralized bone matrix mediates differentiation of bone marrow stromal cells in vitro: effect of age of cell donor. 891 78

Recombinant human bone morphogenetic protein (rhBMP-2) was examined for its in vitro effects on biochemical markers representing osteoblast phenotype. Primary cultures of fetal rat calvarial osteoblasts were used in this study. The results indicated that rhBMP-2 stimulated alkaline phosphatase activity, parathyroid hormone (PTH)-induced cyclic AMP production, and collagen biosynthesis in a dose-dependent manner in confluent cultures. The percent collagen synthesis also increased in a dose-dependent manner. Alkaline phosphatase activity was stimulated in a time-dependent manner by rhBMP-2 that reached its maximum 5 days after initiation. Cycloheximide (2 micrograms/ml) inhibited rhBMP-2-stimulated alkaline phosphatase indicating de novo protein synthesis of the enzyme. Transforming growth factor-beta 1 (TGF-beta 1)-induced inhibition of alkaline phosphatase activity observed in confluent primary cultures was completely abolished by rhBMP-2 at a concentration that was 43 times greater than the TGF-beta 1 concentration. Also, rhBMP-2 produced a small stimulation of alkaline phosphatase activity in cells grown in the absence of ascorbic acid; however, the effect was greatly enhanced in cells cultivated in the presence of ascorbic acid (50 micrograms/ml). In view of the potentiating effect of ascorbic acid on rhBMP-2-induced stimulation of alkaline phosphatase, we speculate that ascorbic acid could amplify the osteoinductive effects of rhBMP-2 and thereby augment the efficacy of the BMP when used as bone repair material in vivo. rhBMP-2 (4.3-86 ng/ml) did not exhibit mitogenic effects on cultured osteoblasts. These data suggest that rhBMP-2 has the ability to induce expression of various markers associated with the osteoblast phenotype in primary cultures of fetal rat calvarial osteoblasts. In addition, we speculate that TGF-beta 1 may play a regulatory role in BMP-induced bone formation and ascorbic acid may potentiate the effects of rhBMP-2 in vivo.
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PMID:Recombinant human bone morphogenetic protein-2 stimulates differentiation in primary cultures of fetal rat calvarial osteoblasts. 905 79


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