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)

Cissus quadrangularis Linn. has been implicated as therapeutic agent for enhancing bone healing. Though its osteogenic activity has been suggested, the underlying mechanism still remains unclear. In the present study, the effects of ethanol extract of C. quadrangularis (CQ-E) on osteoblast differentiation and function were analyzed using murine osteoblastic cells. The results indicated that mRNA expressions of osteoblast-related genes were not affected by the CQ-E treatment. However, alkaline phosphatase (ALP) activity and the extent of mineralized nodules were significantly increased in treated cells compared with controls. The addition of an extracellular regulated kinase 1/2 inhibitor, a Jun N-terminal kinase 1/2/3 inhibitor and a p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in significantly decreased ALP activity, preferentially by p38 MAPK inhibitor. These results suggested that CQ-E may regulate osteoblastic activity by enhancing ALP activity and mineralization process, and the increased ALP activity effect of CQ-E is likely mediated by MAPK-dependent pathway.
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PMID:Cissus quadrangularis extract enhances biomineralization through up-regulation of MAPK-dependent alkaline phosphatase activity in osteoblasts. 1905 68

Strontium ralenate is a new anti-osteoporosis agent. The cellular and molecular mechanism underlying the anabolic effect of strontium on bone remains to be elucidated. Osteoblasts, the main bone forming cells are known to be derived from bone marrow mesenchymal stem cells (MSCs). The present study therefore aimed to investigate the possible effects of strontium on MSCs and signaling pathways possibly involved. It was firstly demonstrated that strontium treatment significantly increased osteoblast-related gene expression and alkaline phosphatase (ALP) of osteogenic-differentiating MSCs. Accompanying the enhanced osteogenic differentiation, the increased phosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2 and p38 was detected in strontium-treated MSCs. PD98059 and SB203580, selective inhibitors of ERK1/2 kinase and p38, attenuated the effect of strontium on osteogenesis. Furthermore, it was demonstrated that Rat Sarcoma viral oncogene homolog (RAS), an upstream regulator of ERK1/2 and p38, was activated by strontium treatment and siRNA-mediated Ras knockdown inhibited strontium-stimulated expression of osteogenic markers. Finally, the transcriptional activity and phosphorylation level of Runx2 was significantly increased in response to strontium treatment in MSCs. PD98059 and Ras siRNA inhibited the effect of strontium on Runx2 activation. Taken together, these results indicated that strontium can promote osteogenic differentiation of MSCs through activating the Ras/MAPK signaling pathway and the downstream transcription factor Runx2.
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PMID:Strontium promotes osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway. 1925 11

We examined the hypothesis that human mesenchymal stem cells detect physiological mechanical signals. Human bone marrow stromal cells (HBMSCs) were exposed to fluid shear stress of 12 dynes/cm(2) and analysed for their ability to express osteoblast-specific markers and associated signalling pathways. HBMSCs showed a significant increase in alkaline phosphatase (ALP) gene expression and a marked decrease in type I collagen, while no effect on Cbfa1/Runx2 was detected. This regulation is related to p38 and ERK1/2 activation, although the use of specific inhibitors to these two MAP kinases suggests that ALP mRNA induction is especially dependent on p38 activity, while type I collagen downregulation is ERK1/2-dependent. Interestingly, the expression of connexin43, which is involved in cell-to-cell communication of osteoblastic cells through gap junction formation, and its distribution through the cells, were modified by fluid flow (FF). HBMSCs are sensitive to shear stress and it appears essential to take their responsiveness into consideration before associating these regenerative cells with a bioactive biomaterial in a new bone tissue-engineering strategy.
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PMID:Responsiveness of human bone marrow stromal cells to shear stress. 1928 26

Electrical stimulation (ES) can activate diverse biostimulatory responses in a range of tissues. Of various forms of ES, the application of biphasic electric current (BEC) is a new approach to bone formation. This study is to investigate the effects and mechanism of action of BEC in osteoblast differentiation and cytokine production in human mesenchymal stromal cells (hMSCs). Using an in vitro culture system with a modified version of the BEC stimulator chip used in our previous study, we exposed hMSCs to a 100 Hz ES with a magnitude of 1.5/15 muA/cm(2) for 250/25 mus. hMSCs showed increased proliferation during static BEC stimulation for 5 days. However, alkaline phosphatase activity and calcium deposition were enhanced in hMSCs 7 days after the stimulation, rather than during the period of ES. BEC induced vascular endothelial growth factor (VEGF) and BMP-2 production; the former can enhance the proliferation of human umbilical vein endothelial cells in culture using conditioned media from BEC cultures. Treatment with selective inhibitors of p38 MAPK (SB203580) or Erk (PD98059), as well as calcium channel blockers (verapamil and nifedipine), reduced the BEC-mediated increase of VEGF expression and cell proliferation. These findings reveal that BEC is involved in the osteoblast differentiation of hMSCs through enhancement of cell proliferation and modulation of the local endocrine environment through VEGF and BMP-2 induction through the activation of MAPK (Erk and p38) and the calcium channel. Thus, local stimulation using BEC might be most beneficial in promoting osteogenic differentiation of hMSCs, resulting in enhanced bone formation for bone tissue engineering.
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PMID:Novel effect of biphasic electric current on in vitro osteogenesis and cytokine production in human mesenchymal stromal cells. 1929 69

In medicine, N-methyl pyrrolidone (NMP) has a long track record as a constituent in medical devices approved by the Food and Drug Administration and thus can be considered as a safe and biologically inactive small chemical. In the present study, we report on the newly discovered pharmaceutical property of NMP in enhancing bone regeneration in a rabbit calvarial defect model in vivo. At the cellular level, the pharmaceutical effect of NMP was confirmed, in particular, in combination with bone morphogenetic protein (BMP)-2, because NMP increased early and late markers for maturation of preosteoblasts and human bone marrow-derived stem cells in vitro. When we used the multipotent cell line C2C12 without autologous BMP expression, NMP alone had no effect on alkaline phosphatase activity, a marker for osteogenic transdifferentiation. Nevertheless, in combination with low BMP-2 doses, alkaline phosphatase activity was more than eight times as great. Thus, the pharmaceutical NMP mode of action is that of an enhancer of BMP activity. The dependency of the effects of NMP on BMP was confirmed in preosteoblasts because noggin, an extracellular BMP inhibitor, suppressed NMP-induced increases in early markers for osteoblast maturation in vitro. At the molecular level, NMP was shown to have no effect on the binding of BMP-2 to the ectodomain of the high-affinity BMP receptor IA. However, NMP further increased the phosphorylation of p38 and Smad1,5,8 induced by BMP-2. Thus, the small chemical NMP enhances BMP activity by increasing the kinase activity of the BMP receptor complex for Smad1,5,8 and p38 and could be employed as a potent drug for bone tissue regeneration and engineering.
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PMID:N-methyl pyrrolidone as a potent bone morphogenetic protein enhancer for bone tissue regeneration. 1932 May 43

Arthritis is one of the most prevalent chronic inflammatory diseases, and it is characterized by structural and biochemical changes in major tissues of the joint, including degradation of the cartilage matrix, insufficient synthesis of extracellular matrix (ECM). Ecklonia cava (EC) is a member of the family of Laminariaceae, which is an edible marine brown alga with various bioactivities. In this study of the methanol extract of brown alga EC, the dieckol (1) and 1-(3',5'-dihydroxyphenoxy)-7-(2'',4'',6''-trihydroxyphenoxy) 2,4,9-trihydroxydibenzo-1,4,-dioxin (2) were isolated and characterized by NMR techniques with high yield. Phlorotannin derivatives (1, 2) promoted osteosarcoma differentiation by increasing alkaline phosphatase (ALP) activity, mineralization, total protein and collagen synthesis in human osteosarcoma cell (MG-63 cells), respectively. Furthermore, these phlorotannin derivatives (1, 2) inhibited mRNA gene and protein levels of matrix metalloproteinase (MMP-1, MMP-3, and MMP-13), iNOS and COX-2 in casein zymography, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) assays. In addition, it was observed that the phlorotannins inhibited phosphorylation of JNK and p38 MAPK in human osteosarcoma cell. These results suggested the phlorotannin derivatives (1, 2) could promote cell differentiation, attenuate MMP-1, MMP-3, MMP-13 expressions, and inflammatory response via MAPK pathway in chronic articular diseases.
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PMID:Differentiation of human osteosarcoma cells by isolated phlorotannins is subtly linked to COX-2, iNOS, MMPs, and MAPK signaling: implication for chronic articular disease. 1933 Aug 80

Preptin, a newly isolated 34-amino-acid peptide hormone that is cosecreted with insulin and amylin from pancreatic beta-cells, has emerged as a regulatory element in bone metabolism, but its mechanism remains unclear. We assessed the effects of preptin on proliferation and differentiation of human osteoblasts and investigated the mechanism involved. Our results demonstrated that preptin promoted human osteoblasts proliferation and alkaline phosphatase activity. Suppression of connective tissue growth factor (CTGF), which was upregulated by preptin in a dose- and time-dependent manner, with small interfering RNA (siRNA) abolished the preptin-induced human osteoblasts proliferation and differentiation. Preptin induced activation of ERK mitogen-activated protein kinase (MAPK), but not p38 or JNK in human osteoblasts. Furthermore, pretreatment of human osteoblasts with the ERK inhibitor PD98059 abolished the preptin-induced CTGF secretion and blocked the promoting effect of preptin on osteoblasts proliferation and differentiation. These data demonstrated that preptin is involved in bone anabolism mediated by ERK/CTGF in human osteoblasts and may contribute to the preservation of bone mass observed in hyperinsulinemic states, such as obesity.
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PMID:Connective tissue growth factor is a downstream mediator for preptin-induced proliferation and differentiation in human osteoblasts. 1933 18

Relatively few studies have examined the effects of formula feeding relative to breast-feeding on bone in the neonate. Using peripheral quantitative CT scan and histomorphometric analysis, we demonstrated that neonatal piglets fed with soy-based formula (SF) and cow milk-based formula (MF) for 21 or 35 d had greater bone mineral density and content than breast-fed piglets (BF) (P < 0.05). Osteoblast numbers and bone formation rate at postnatal d 35 were greater in SF compared with other groups (P < 0.05), whereas osteoclast numbers were lower in both MF and SF groups than in the BF group (P < 0.05). Osteoblastogenesis was greater in ex vivo bone marrow cell cultures from SF than in MF or BF piglets (P < 0.05). Bone formation markers in serum were greater, whereas bone resorption markers were lower in the MF- and SF-fed groups than in the BF group (P < 0.05). Bone morphogenic protein (BMP) 2 and alkaline phosphatase mRNAs were upregulated in the MF and SF groups compared with the BF group (P < 0.05), whereas receptor activator of NF-kappaB ligand was downregulated (P < 0.05). Extracellular signal-regulated kinase, p38, Smad1/5/8 phosphorylation, and runt-related transcription factor 2 expression were greater in bone from the MF and SF groups compared with the BF group (P < 0.05). In vitro studies showed that 2.5% serum from SF- or MF-fed piglets was able to stimulate osteoblast differentiation but not in the presence of the BMP blocker noggin. Therefore, formula feeding promoted bone growth compared with BF. SF piglets had the highest bone volume over tissue volume. This suggests that SF-fed piglets may have the best quality bone. The anabolic effects of SF on bone appear to be mediated through enhanced BMP signaling.
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PMID:Infant formula promotes bone growth in neonatal piglets by enhancing osteoblastogenesis through bone morphogenic protein signaling. 1971 Jan 59

Natural compounds with bone-forming (or anabolic) activity have been recently focused on in bone research. The present study investigated the effect of undecylenic acid (UA) on osteoblast differentiation in mouse osteoblastic MC3T3-E1 subclone 4 cells and primary mouse calvarial cells. Low concentrations of UA (up to 5 microM) exhibited no cytotoxicity and significantly increased the expression and activity of alkaline phosphatase (early differentiation marker of osteoblast) and calcium deposition with the induction of expression of the osteocalcin gene in both cells. Interestingly, at low concentration of UA, the induction of NF-kappaB p65 translocation into nucleus and the up-regulation of AP-1 and NFATc1 transcript levels were also observed, suggesting that the stimulatory effect of UA on osteoblast differentiation could be mediated through the activation of transcription factors. Additionally, although the patterns of UA-induced activation of MAP kinases (JNK and p38) were not completely consistent with the increase of both ALP activity and calcium deposition by UA, MAP kinases might be partially involved in the biological function of UA during the early and late stages of osteoblast differentiation.
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PMID:Stimulatory effect of undecylenic acid on mouse osteoblast differentiation. 1977 59

Pro-forms of growth factors have received increasing attention since it was shown that they can affect both the maturation and functions of mature growth factors. Here, we assessed the biological function of the pro-form of bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor beta (TGFbeta)/BMP superfamily. The role of the 263 amino acids of the pro-peptide is currently unclear. In order to obtain an insight into the function of the pro-form (proBMP-2), the ability of proBMP-2 to induce alkaline phosphatase (AP), a marker enzyme for cells differentiating into osteoblasts, was tested. Interestingly, in contrast to mature BMP-2, proBMP-2 did not lead to induction of AP. Instead, proBMP-2 inhibited the induction of AP by BMP-2. This result raised the question of whether proBMP-2 may compete with mature BMP-2 for receptor binding. ProBMP-2 was found to bind to the purified extracellular ligand binding domain (ECD) of BMPR-IA, a high-affinity receptor for mature BMP-2, with a similar affinity as mature BMP-2. Binding of proBMP-2 to BMPR-IA was confirmed in cell culture by cross-linking proBMP-2 to BMPR-IA presented on the cell surface. In contrast to this finding, proBMP-2 did not bind to the ECD of BMPR-II. ProBMP-2 also differed from BMP-2 in its capacity to induce p38 and Smad phosphorylation. The data presented here suggest that the pro-domain of BMP-2 can alter the signalling properties of the growth factor by modulating the ability of the mature part to interact with the receptors.
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PMID:The pro-form of BMP-2 interferes with BMP-2 signalling by competing with BMP-2 for IA receptor binding. 1980 12


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