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)

Experiments have been carried out to determine the mechanisms involved in the formation of osteoclast-like cells from spleen cells in mice. Osteoclasts were defined as tartrate-resistant acid phosphatase-positive multinucleated cells (TRACP-positive MNCs) in which specific calcitonin receptors were identified by autoradiography with labeled salmon calcitonin. Furthermore, cultures rich in these cells produced resorption pits when grown on dentine slices. Several clonal cell lines were obtained from fetal mouse calvariae and screened for their ability to induce TRACP-positive MNCs in response to 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25(OH)2D3] in co-cultures with spleen cells. A cell line, KS-4, was identified with the greatest potency in inducing osteoclast-like cell formation in co-culture with spleen cells. The capacity of KS-4 cells to produce this effect was much greater than that of two bone marrow-derived stromal cell lines (MC3T3-G2/PA6 and ST2 cells), which we have previously shown to be effective in this system but to require treatment with dexamethasone in addition to 1 alpha, 25(OH)2D3 (Udagawa et al.: Endocrinology 125:1805-1813, 1989). Parathyroid hormone (PTH) increased cAMP production in KS-4 cells, and PTH and interleukin-1 alpha also induced TRACP-positive MNCs in co-cultures with spleen cells. Contact between living KS-4 and spleen cells was necessary for osteoclast formation to take place, since this did not occur when the two populations were separated by a membrane filter, or when the KS-4 cells were killed by fixation. Separate cultures of either spleen cells or KS-4 cells formed no TRACP-positive MNCs. KS-4 cells synthesized predominantly type I collagen, formed bone nodules without added of beta-glycerophosphate in a long-term culture, and expressed increasing alkaline phosphatase activity after confluence in culture. These results indicate that the KS-4 cells have properties consistent with progression toward the osteoblast phenotype and represent a single cell line with the ability to promote osteoclast formation by a contact-requiring process.
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PMID:Cloning of an osteoblastic cell line involved in the formation of osteoclast-like cells. 170 73

A clone of a human Bone Morphogenetic Protein-2 (hBMP-2) cDNA was obtained from a cDNA library established from human dental pulp cells. After subcloning hBMP-2 cDNA into Autographa californica nuclear polyhedrosis virus, the recombinant baculovirus was transfected to Sf-9 cells. Immuno-reactive recombinant hBMP-2 (rhBMP-2) was detected by a polyclonal antibody against Xenopus BMP-2 in the transfected insect cells but not in the culture media. Three days after treatment with the lysate of the transfected Sf-9 cells, increase in alkaline phosphatase activity of a murine stromal cell line, ST2, was detected. Subcutaneous implantation of rhBMP-2 produced in the insect cells induced formation of cartilage, bone and bone marrow in the rats. The present data indicated that the rhBMP-2 preparation produced in the insect Sf-9 cells had a comparable activity to that produced in mammalian cells.
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PMID:Production of functional human bone morphogenetic protein-2 using a baculovirus/Sf-9 insect cell system. 754 38

Basic fibroblast growth factor (bFGF) inhibited osteoclast-like cell formation in co-cultures of mouse bone marrow cells either with the mouse stromal cell line, ST2, or with primary osteoblastic cells. Basic FGF significantly inhibited the osteoclast-like cell formation, induced by 1 alpha,25-dihydroxyvitamin D3[1 alpha, 25(OH)2D3] when the cytokine was added to the culture, at an intermediate stage, suggesting that bFGF inhibits the differentiation of the osteoclast progenitors. With regard to target cells, bFGF directly affected ST2; it increased [3H] thymidine uptake and decreased the number of alkaline phosphatase-positive cells. In contrast, bFGF had no inhibitory effect on the colony formation of bone marrow cells induced by macrophage colony stimulating factor in methylcellulose culture. In addition, ST2 cells treated with bFGF produced similar amounts of colony forming activity to those without the cytokine. These findings indicated that the bFGF is not involved in the proliferation of progenitor cells even in the presence of ST2 cells. Furthermore, bFGF inhibited osteoclast-like cell formation induced not only by 1 alpha,25(OH)2D3, but also by prostaglandin E2 and by interleukin-11. These results suggest that bFGF inhibits the common site of osteoclast-like cell formation, as induced by different mechanisms. Our data also indicated that the target cells for bFGF in inhibiting osteoclast formation are not osteoclast progenitors but stromal cells such as ST2 and osteoblastic cells, which support osteoclast development.
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PMID:Basic fibroblast growth factor inhibits osteoclast-like cell formation. 870 75

Bone morphogenetic proteins (BMPs) are multifunctional proteins that comprise the largest subfamily of the transforming growth factor-beta. These proteins bind to types I and II serine/threonine kinase receptors. Ligand-induced heteromeric dimerization of these receptors is the key event in initiation of biological responses. We report here large-scale expression and purification of extracellular domain of the type I receptor for BMP-2/4, using a silkworm expression system. This soluble form of BMP receptor (sBMPR) was in monomer form in solution and bound to BMP-4 but not to activin or transforming growth factor-beta1. Surface plasmon resonance studies showed that kinetic parameters of sBMPR for BMP-4 consisted of a relatively rapid association rate constant (ka = 3.81 +/- 0.19 x 10(4) s-1 M-1) and an extremely slow dissociation rate constant (kd = 3.69 +/- 0.26 x 10(-4) s-1). From these two kinetic parameters, affinity was determined to be similar to that of the intact membrane-associated receptor expressed on COS cells. sBMPR inhibited the alkaline phosphatase activity in BMP responsive cell lines such as mouse osteoblastic cell MC3T3-E1 and bone marrow stromal cell ST2. These data indicate that the extracellular domain of type I receptor for BMP-2 and BMP-4 is sufficient for high-affinity binding to its ligands and should prove useful in understanding the role of BMP-2/4 in vivo, because a suitable high-affinity anti-BMP antibody has yet to be developed.
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PMID:Interaction between soluble type I receptor for bone morphogenetic protein and bone morphogenetic protein-4. 911 Oct 68

The stromal cell line ST2, derived from mouse bone marrow, differentiated into osteoblast-like cells in response to ascorbic acid. Ascorbic acid induced alkaline phosphatase (ALPase) activity, the expression of mRNAs for proteins that are markers of osteoblastic differentiation, the deposition of calcium, and the formation of mineralized nodules by ST2 cells. We investigated the mechanism whereby ascorbic acid induced the differentiation of ST2 cells. Inhibitors of the formation of collagen triple helices completely blocked the effects of ascorbic acid on ST2 cells, an indication that matrix formation by type I collagen is essential for the induction of osteoblastic differentiation of ST2 cells by ascorbic acid. We furthermore examined the effects of bone morphogenetic proteins (BMPs) on the differentiation of ST2 cells induced by ascorbic acid. Ascorbic acid had no effect on the expression of mRNAs for BMP-4 and the BMP receptors. However, a soluble form of BMP receptor IA inhibited the induction of ALPase activity by ascorbic acid. These results suggest that ascorbic acid might promote the differentiation of ST2 cells into osteoblast-like cells by inducing the formation of a matrix of type I collagen, with subsequent activation of the signaling pathways that involve BMPs.
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PMID:Characterization of osteoblastic differentiation of stromal cell line ST2 that is induced by ascorbic acid. 1040 16

The acute effects of nicotine [1-methyl-2-(3-pyridyl)pyrrolidine] on the formation and resorption of bone were examined in cultures of clonal rat calvarial osteogenic cells (ROB-C26) and clonal mouse calvarial preosteoblastic cells (MC3T3-E1), as well as in osteoclast-like cells formed during coculture of mouse bone marrow cells and clonal stromal cells from mouse bone marrow, ST2 cells, at concentrations that occur in the saliva of smokeless tobacco users. Nicotine stimulated the rate of deposition of Ca(2+) by ROB-C26 cells, as well as the alkaline phosphatase activity of these cells, in a dose-dependent manner. However, both activities decreased in MC3T3-E1 cells that had been exposed to nicotine. These results indicate that nicotine affected osteoblastic differentiation in osteoblast-like cells. By contrast, nicotine reduced, in a dose-dependent manner, the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) and the formation of pits on slices of dentine, both of which are typical characteristics of osteoclasts. Our results suggest that nicotine might have critical effects on bone metabolism.
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PMID:Effects of nicotine on cultured cells suggest that it can influence the formation and resorption of bone. 1059 33

Morphologically macrophage-like cells were cloned from hamster bone marrow cells by coculturing bone marrow cells with hamster chondrocytes. One of the clones (CCP-2) was characterized in the present study. CCP-2 cells were positive in an osteoclast marker enzyme, tartrate-resistant acid phosphatase (TRAP), alkaline phosphatase (ALP) and non-specific esterase (NSE). We showed CCP-2 cells degraded cartilage matrix and hydroxyapatite coated on Osteologic disks. A gelatinase secreted from CCP-2 cells was observed and purified from serum-free conditioned medium of the cells. N-terminal amino acid sequencing of the purified enzyme revealed it was matrix metalloproteinase-9. However, CCP-2 cells failed to express calcitonin receptors, a mature osteoclast marker, even after coculture with osteoblast ST2 cells in the presence of 1alpha, 25-dihydroxyvitamin D3 [1alpha, 25-(OH)2D3]. The cells showed high affinity to types X and I but not to type II collagen. In addition, histochemical studies have shown the presence of tartrate-resistant acid phosphatase and alkaline phosphatase double positive cells at the secondary ossification site of the hamster humerus. From these observations, we concluded that CCP-2 cells are similar to osteoclast but not the same. CCP-2 cells are therefore important tools for investigating chondroclastogenesis/osteoclastogenesis and endochondral ossification.
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PMID:Establishment and characterization of tartrate-resistant acid phosphatase and alkaline phosphatase double positive cell lines. 1145 11

The proteins of the hedgehog (Hh) family regulate various aspects of development. Recently, members of this family have been shown to regulate skeletal formation in vertebrates and to control both chondrocyte and osteoblast differentiation. In the present study, we analyzed the effect of Sonic hedgehog (Shh) on the osteoblastic and adipocytic commitment/differentiation. Recombinant N-terminal Shh (N-Shh) significantly increased the percentage of both the pluripotent mesenchymal cell lines C3H10T1/2 and ST2 and calvaria cells responding to bone morphogenetic protein 2 (BMP-2), in terms of osteoblast commitment as assessed by measuring alkaline phosphatase (ALP) activity. This synergistic effect was mediated, at least partly, through the positive modulation of the transcriptional output of BMPs via Smad signaling. Furthermore, N-Shh was found to abolish adipocytic differentiation of C3H10T1/2 cells both in the presence or absence of BMP-2. A short treatment with N-Shh was sufficient to dramatically reduce the levels of the adipocytic-related transcription factors C/EBPalpha and PPARgamma in both C3H10T1/2 and calvaria cell cultures. Given the inverse relationship between marrow adipocytes and osteoblasts with aging, agonists of the Hh signaling pathway might constitute potential drugs for preventing and/or treating osteopenic disorders.
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PMID:Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. 1149 44

Retinoids are known to be of special importance for normal bone growth and development. Recently, we reported that retinoids not only induced osteoblast differentiation, but also inhibited osteoclast formation in vitro. In this study, we examined the osteogenic effects of geranylgeranoic acid (GGA), a chemically synthesized acyclic retinoid, in bone in vitro and in vivo. GGA not only suppressed proliferation of osteoblastic MC3T3-E1 cells, but also up-regulated differentiation markers of osteoblasts such as alkaline phosphatase (ALP) activity and expression of osteopontin (OP) messenger RNA (mRNA). In contrast, GGA inhibited osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] in cocultures of mouse bone marrow cells and primary osteoblasts. Treatment of stromal ST2 cells with GGA restored the 1alpha,25(OH)2D3- or prostaglandin E2 (PGE2)-induced suppression of osteoprotegerin (OPG) mRNA expression. GGA inhibited osteoclast formation induced by macrophage colony-stimulating factor (M-CSF) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in the culture of bone marrow macrophages. Thus, it is likely that GGA inhibits osteoclast formation by affecting both osteoblasts and osteoclast progenitors in the coculture system. Furthermore, in vivo, GGA increased bone mineral density (BMD) of total as well as distal femur in a P6 strain of senescence-accelerated mice (SAMP6). These results indicate that GGA increases bone mass by maintaining a positive balance of bone turnover by inducing osteoblast differentiation and suppressing osteoclast formation.
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PMID:Effects of geranylgeranoic acid in bone: induction of osteoblast differentiation and inhibition of osteoclast formation. 1177 73

The cyclic monophosphate nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) are found ubiquitously in mammalian cells and act as second messenger transducers to effect the intracellular actions of a variety of hormones, cytokines, and neurotransmitters. In turn, these nucleotides also modulate the signal transduction processes regulated by a range of cytokines and growth factors. Previously, we have reported that pentoxifylline, a nonselective phosphodiesterase (PDE) inhibitor, can promote osteoblastic differentiation by elevating intracellular cAMP levels and, consequently, enhance bone formation in vivo and in vitro. In this study, reverse-transcription polymerase chain reaction (RT-PCR) analysis of the osteoblastic cell lines, MC3T3-E1 and ST2 revealed the presence of PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, and PDE9. We examined the effect of selective inhibitors for a respective PDE isozyme on the capacity of bone morphogenetic protein 4 (BMP-4)-induced alkaline phosphatase (ALP) activity, a cellular differentiation marker, in cells with osteogenetic potential. The results indicate that selective inhibitors for PDE2, PDE3, and PDE4 enhanced the BMP-4-induced ALP activity in a dose-dependent manner in ST2 cells but not in MC3T3-E1 cells. Northern blot analysis also revealed that the selective inhibitors for PDE2, PDE3, and PDE4 enhanced the levels of expression of messenger RNAs (mRNAs) of ALP, osteopontin (OP), and collagen type I in ST2 cells but not in MC3T3-E1 cells except for the treatment with PDE4 inhibitor. Given these data, we conclude that PDE isozymes are involved in the modulation of osteoblastic differentiation mainly at an early stage. Additionally, selective inhibitors for PDE2, PDE3, and PDE4 appear to promote the differentiation of osteogenic precursor cells toward an osteoblastic phenotype.
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PMID:Involvement of phosphodiesterase isozymes in osteoblastic differentiation. 1181 55


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