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)

Interleukin-4 (IL-4) inhibits the spontaneous and stimulated bone resorption resulting from the inhibition of osteoclast formation, as well as osteoclastic activity. Since IL-13 shares some biological properties with IL-4, it was recently reported that IL-13 inhibits bone resorption. The present study was designed to determine the effects of murine IL-4 (IL-4) and murine IL-13 (IL-13) on the murine osteoblastic cell line MC3T3-E1. IL-4 and IL-13 stimulated 3H-thymidine incorporation in the MC3T3-E1 cells and its proliferation in dose dependent manners. A spontaneous increase in alkaline phosphatase (ALP) activity in the cells after plating was inhibited by IL-4 or IL-13, and both cytokines blunted an increase in ALP activity by human parathyroid hormone (PTH) (1-34). PTH-stimulated cyclic AMP (cAMP) production was inhibited by pretreatment with IL-4 and IL-13 for 48 hr in dose dependent manners. Pretreatment with IL-4 and IL-13 for 48 hr caused a decrease in PTH-induced cAMP production at any stimulatory concentration. However, the effective dose (ED50) was unchanged by the pretreatment with these cytokines. Pretreatment with IL-4 and IL-13 did not modulate cAMP generation by forskolin. In contrast, cAMP generation by PGE2 is greater in the cells treated with the cytokines compared to those without the cytokines. These results indicate that IL-4 and IL-13 act on MC3T3-E1 cells in the same manner, stimulating cell proliferation, but inhibiting cell differentiation. The inhibition of osteoblast differentiation by IL-4 and IL-13 may be associated with a decrease in PTH actions on osteoblasts.
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PMID:Interleukin (IL)-4 and IL-13 inhibit the differentiation of murine osteoblastic MC3T3-E1 cells. 1103 73

Pulsed electromagnetic field stimulation has been used to promote the healing of chronic nonunions and fractures with delayed healing, but relatively little is known about its effects on osteogenic cells or the mechanisms involved. The purpose of this study was to examine the response of osteoblast-like cells to a pulsed electromagnetic field signal used clinically and to determine if the signal modulates the production of autocrine factors associated with differentiation. Confluent cultures of MG63 human osteoblast-like cells were placed between Helmholtz coils and exposed to a pulsed electromagnetic signal consisting of a burst of 20 pulses repeating at 15 Hz for 8 hours per day for 1, 2, or 4 days. Controls were cultured under identical conditions, but no signal was applied. Treated and control cultures were alternated between two comparable incubators and, therefore, between active coils; measurement of the temperature of the incubators and the culture medium indicated that application of the signal did not generate heat above the level found in the control incubator or culture medium. The pulsed electromagnetic signal caused a reduction in cell proliferation on the basis of cell number and [3H]thymidine incorporation. Cellular alkaline phosphatase-specific activity increased in the cultures exposed to the signal, with maximum effects at day 1. In contrast, enzyme activity in the cell-layer lysates, which included alkaline phosphatase-enriched extracellular matrix vesicles, continued to increase with the time of exposure to the signal. After 1 and 2 days of exposure, collagen synthesis and osteocalcin production were greater than in the control cultures. Prostaglandin E2 in the treated cultures was significantly reduced at 1 and 2 days, whereas transforming growth factor-beta1 was increased; at 4 days of treatment, however, the levels of both local factors were similar to those in the controls. The results indicate enhanced differentiation as the net effect of pulsed electromagnetic fields on osteoblasts, as evidenced by decreased proliferation and increased alkaline phosphatase-specific activity, osteocalcin synthesis, and collagen production. Pulsed electromagnetic field stimulation appears to promote the production of matrix vesicles on the basis of higher levels of alkaline phosphatase at 4 days in the cell layers than in the isolated cells, commensurate with osteogenic differentiation in response to transforming growth factor-beta1. The results indicate that osteoblasts are sensitive to pulsed electromagnetic field stimulation, which alters cell activity through changes in local factor production.
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PMID:Pulsed electromagnetic field stimulation of MG63 osteoblast-like cells affects differentiation and local factor production. 1105 1

Prostaglandin E(2) (PGE(2)) has been shown to exert a bone anabolic effect in young and adult rats. In this study we tested whether it possesses a similar effect on bone formation and bone mass in aging rats. Fifteen-month-old rats were injected daily with either PGE(2) at 5 mg/kg or vehicle for 14 days. PGE(2) treatment stimulated the rate of cancellous bone formation (a approximately 5.5-fold increase in bone formation rate), measured by the incorporation of calcein into bone-forming surfaces at the tibial proximal metaphysis. This effect resulted in increased cancellous bone area (+54%) at the same site. Since PGE(2) treatment resulted in a much higher proportion of bone surface undergoing bone formation and thus lined with osteoblasts, we tested the hypothesis that PGE(2) stimulates osteoblast differentiation from bone marrow precursor cells both in vivo and in vitro. We found that ex vivo cultures of bone marrow stromal cells from rats injected for 2 weeks with PGE(2) at 5 mg/kg per day yielded more ( approximately 4-fold) mineralized nodules and exhibited a greater (by 30-40%) alkaline phosphatase activity compared with cultures from vehicle-injected rats, attesting to a stimulation of osteoblastic differentiation by PGE(2). We also compared the osteogenic capacity of bone marrow from aging (15-month-old) versus young (5-week-old) rats and its regulation by PGE(2) in vitro. Bone marrow stromal cell cultures from aging rats exhibited a greatly diminished osteogenic capacity, reflected in reduced nodule formation ( approximately 6% of young animals) and lower alkaline phosphatase activity ( approximately 60% of young animals). However, these parameters could be stimulated in both groups of animals by incubation with 10-100 nM PGE(2). The magnitude of this stimulation was greater in cultures from aging rats (+550% vs +70% in nodule formation of aging compared with young rats). In conclusion, we demonstrate here that PGE(2) exerts a bone anabolic effect in aging rats, similar to the effect we and others have reported in young, growing rats. The PGE(2)-stimulated bone formation, which augments bone mass, most likely results from recruitment of osteoblasts from their bone marrow stromal precursors.
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PMID:Systemic prostaglandin E2 increases cancellous bone formation and mass in aging rats and stimulates their bone marrow osteogenic capacity in vivo and in vitro. 1113 77

Intracellular signals generated by mechanical strain profoundly affect the metabolic function of osteoblast-like periodontal ligament (PDL) cells, which reside between the tooth and alveolar bone. In response to applied mechanical forces, PDL cells synthesize bone-resorptive cytokines to induce bone resorption at sites exposed to compressive forces and deposit bone at sites exposed to tensile forces in an environment primed for catabolic processes. The intracellular mechanisms that regulate this bone remodeling remain unclear. Here, in an in vitro model system, we show that tensile strain is a critical determinant of PDL-cell metabolic functions. Equibiaxial tensile strain (TENS), when applied at low magnitudes, acts as a potent antagonist of interleukin (IL)-1beta actions and suppresses transcriptional regulation of multiple proinflammatory genes. This is evidenced by the fact that TENS at low magnitude: (i) inhibits recombinant human (rh)IL-1beta-dependent induction of cyclooxygenase-2 (COX-2) mRNA expression and production of prostaglandin estradiol (PGE2); (ii) inhibits rhIL-1beta-dependent induction matrix metalloproteinase-1 (MMP-1) and MMP-3 synthesis by suppressing their mRNA expression; (iii) abrogates rhIL-1beta-induced suppression of tissue inhibitor of metalloprotease-II (TIMP-II) expression; and (iv) reverses IL-1beta-dependent suppression of osteocalcin and alkaline phosphatase synthesis. Nevertheless, these actions of TENS were observed only in the presence of IL-1beta, as TENS alone failed to affect any of the aforementioned responses. The present findings are the first to show that intracellular signals generated by low-magnitude mechanical strain interfere with one or more critical step(s) in the signal transduction cascade of rhIL-1beta upstream of mRNA expression, while concurrently promoting the expression of osteogenic proteins in PDL cells.
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PMID:Signaling by mechanical strain involves transcriptional regulation of proinflammatory genes in human periodontal ligament cells in vitro. 1193 44

Rats were given 5 kinds of diets which contained 15% (w/w) fat and different fatty acids composition. The rats were given methyl-nitrosurea (MNU) to induce colonic tumor. Proliferation cell nuclear antigen (PCNA), cell kinetics, membrane fluidity, the activity of alkaline phosphatase (ALP) and the content of prostaglandin E2(PGE2) in colonic mucosa were determined in order to assess the fatty acids composition on the colonic cell tumorigenesis. The results indicated that the cells of PCNA, cells of PI labeled in S period and the activity of ALP were the highest in the 3rd group which contained lowest saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) and highest n-6 polyunsaturated fatty acids. Whereas, these indexes and PGE2 were lowest and membrane fluidity was the best in the 4th group which contained the highest 1-3 PUFA. It is considered that the inhibition tumorigenesis of n-3 PUFA may be related to its effects of decreaing PCNA, PGE2, cells in S period and increasing membrane fluidity.
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PMID:[Research on the mechanism of the fatty acid composition on the tumorigenic danger induced by chemical tumorigenic material]. 1193 97

The effect of phosphogenistein and phosphodaidzein, which are phosphorylated for the hydroxyl group (OH) at the 7-position of genistein and daidzein, on bone components was investigated. Femoral-metaphyseal tissues obtained from male rats (4 weeks old) were cultured for 24-72 h in Dulbecco's modified Eagle's medium (high glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. The presence of phosphogenistein (10(-5) M) caused a significant increase in calcium content, alkaline phosphatase activity, and deoxyribonucleic acid (DNA) content in bone tissues cultured for 24 h. Phosphodaidzein (10(-5) M) significantly elevated bone calcium and DNA content. These effects were completely prevented by the presence of cycloheximide (10(-6) M), an inhibitor of protein synthesis. When femoral-metaphyseal tissues were cultured for 48 h in the presence of parathyroid hormone (1-34) (PTH; 10(-8) M) or prostaglandin E2 (PGE2; 10(-6) M), bone calcium content was significantly decreased. This decrease was significantly blocked by the presence of phosphogenistein (10(-6) and 10(-5) M) or phosphodaidzein (10(-6) and 10(-5) M). The presence of PTH (10(-8) M) or PGE2 (10(-6) M) caused a significant increase in glucose consumption and lactic acid production by bone tissues. These increases were significantly inhibited by the presence of phosphogenistein (10(-5) M) or phosphodaidzein (10(-5) M), indicating their inhibitory effect on bone resorption. The present study has demonstrated that both phosphogenistein and phosphodaidzein have an anabolic effect on bone metabolism in rat femoral-metaphyseal tissues in vitro.
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PMID:Anabolic effect of phosphogenistein and phosphodaidzein on bone components in rat femoral-metaphyseal tissues in vitro. 1198 97

Prostaglandins E (PGEs) are abundantly produced in the skeletal tissue, the turnover of which they can modulate acting on both bone deposition and resorption. We compared the effects of PGE1 and PGE2 on the growth and differentiation of rat bone-marrow osteoblast-like cells cultured in vitro. Both PGEs stimulated cultured cell growth, PGE2 being more effective than PGE1. PGE1 inhibited and PGE2 enhanced alkaline phosphatase activity. Both PGEs markedly raised osteocalcin synthesis, without apparently affecting collagenase-digestible protein production. Scanning electron microscopy showed that untreated cultured osteoblast-like cells were arranged in clusters and displayed a polygonal shape. PGE1 did not alter cell morphology, while PGE2 provoked elongation of cultured cells and sprouting of slend cytoplasmic processes. Morphometric analysis indicated that PGE1 decreased and PGE2 increased cultured-cell dimensions. Collectively, these findings allow us to conclude that PGE1 and PGE2, although being both able to enhance proliferation of osteoblast-like cells cultured in vitro, exert divergent effects on their differentiation. PGE1 seems to slow-down osteoblast maturation, while PGE2 appears to stimulate osteoblast differentiation to mature osteocytes.
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PMID:Effects of prostaglandins E1 and E2 on the growth and differentiation of osteoblast-like cells cultured in vitro. 1223 92

The underlying mechanisms responsible for both cartilage loss and subchondral bone changes in osteoarthritis (OA) remain unknown. It is becoming recognized that the extracellular matrix influences the metabolism of cells both in vivo and in vitro and can modify their responses to external stimuli. Indeed, the glycosaminoglycan/proteoglycan matrix is of major importance for the proliferation and/or differentiation of a number of cells. Here, we determined the potential role of hyaluronic acid (HA) of increasing molecular weight (MW) to alter the expression of metabolic markers and cytokine production by human osteoarthritic (OA) subchondral osteoblasts (Ob). Both 1,25(OH)(2)D(3)-induced alkaline phosphatase activity (ALPase) and osteocalcin release were increased in OA Ob when compared to normal. HA reduced osteocalcin release in OA Ob at MW of 300 and above, whereas HA failed to significantly modify ALPase. Parathyroid hormone (PTH) stimulated cyclic AMP (cAMP) formation by OA Ob. HA had a biphasic effect on this PTH-dependent activity, totally inhibiting cAMP formation at MW of 300 and 800. HA of increasing MW progressively reduced the levels of Prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) produced by OA Ob. Interestingly, urokinase plasminogen activator (uPA) and and PA inhibitor-1 (PAI-1) levels were not significantly affected by HA of increasing MW; however, the PAI-1 to uPA ratio showed a slight, yet nonsignificant increase. Surprisingly, uPA activity was increased in OA Ob under the same conditions. Last, HA had no effect on the production of insulin-like growth factor-1 by these cells. Our data suggest that high MW HA can modify cellular parameters in OA Ob that are increased when compared to normal. The effect of HA on inflammatory mediators, such as PGE(2) and IL-6, and on uPA activity is more striking at higher MW as well. Taken together, these results could suggest that HA of increasing MW has positive effects on OA Ob by modifying their biological synthetic capacities.
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PMID:Hyaluronic acid reverses the abnormal synthetic activity of human osteoarthritic subchondral bone osteoblasts. 1455 76

Osteoblastic induction is commonly studied using the colony-forming unit-fibroblastic (CFU-f) assay, in which bone marrow stromal cells (BMC) are grown in a tissue culture environment permissive for osteoblastic differentiation (DMEM containing dexamethasone, ascorbic acid and beta-glycerophosphate). These cells form colonies, which express alkaline phosphatase, and form a collagenous matrix that becomes calcified. However, these same cells originate in the bone marrow where under normal circumstances they do not proliferate or differentiate despite being subjected to many of the same growth factors and hormones present within the tissue culture environment. We show here that phenol red, present within tissue culture medium as a pH indicator, may itself be a factor that permits osteoblastic recruitment. BMC cultured in the presence of the bone anabolic agents PGE2, PGA2, or bFGF, but in the absence of phenol red, failed to respond to these agents in terms of total or osteoblastic colony number. This effect was dose dependent, with low (2.5 mg/l) and high (15-20 mg/l) doses of phenol red being nonpermissive for the stimulatory effects of PGE2 whereas doses of 5-10 mg/l were permissive. Furthermore, the effects observed in the absence of phenol red could not be abrogated by the addition of 17beta-estradiol indicating that these effects cannot be attributed to estrogenic impurities within the phenol red preparation. This indicates that phenol red itself can affect the differentiation of BMC by a mechanism not previously described.
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PMID:Effects of phenol red on CFU-f differentiation and formation. 1456 99

Bone morphogenetic protein (BMP) induces bone formation in young rodents, but aging causes a reduction in the bone-forming ability of BMP. Most patients who require bone reconstruction are relatively old. Accordingly, we examined whether anabolic hormones could restore the bone inductive activity of rhBMP-2 in aged rats. rhBMP-2 in a carrier pellet was implanted subcutaneously in both 4- and 50-week-old female Wistar rats. PTH, PGE2, or 1,25(OH)2D3 was injected every day during the period of BMP implantation. The pellets were harvested, and were examined both histologically and biochemically 2 weeks after implantation. Bone-forming ability was measured by alkaline phosphatase (ALP) activity and calcium (Ca) content. Pellets in 50-week-old rats showed a significant reduction in bone formation compared to pellets in 4-week-old rats. However, daily injections of PTH into 50-week-old rats restored both ALP activity (103 +/- 4.6%) and Ca content (105 +/- 2.6%). 1,25(OH)2D3 and PGE2 also restored Ca content (103 +/- 4.5% and 98 +/- 3.8%, respectively) and stimulated ALP activity (142 +/- 2.3% and 133 +/- 3.6%). These results show that the administration of these hormones restores bone-forming ability in aged rats. A combination treatment of these hormones with rhBMP-2 might be applicable to the reconstruction of bone defects in elderly patients.
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PMID:Administration of parathyroid hormone, prostaglandin E2, or 1-alpha,25-dihydroxyvitamin D3 restores the bone inductive activity of rhBMP-2 in aged rats. 1457 6


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