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)

Dentin sialophosphoprotein (DSPP) is an extracellular matrix, typically dentin- and bone-specific gene, which plays an important role in dentin mineralization and tooth development. Adipose-derived stromal cells (ADSCs) are considered to contain a group of pluripotent mesenchymal stem cells which are capable of mineralization either in vitro or in vivo. In the present study, we hypothesized that overexpression of DSPP would promote mineralization in ADSCs. Our results showed that infection of DSPP-expressing adenovirus (Ad-DSPP) enhanced expression of genes related to mineralization, such as Cbfa1,Osx,BSP, OCN and DMP1 in ADSCs. Alkaline phosphatase activity was also confirmed in Ad-DSPP-infected ADSCs by cytochemistry and alkaline phosphatase activity assay. Mineralization assay indicated that Ad-DSPP-infected ADSCs were able to form mineralized nodules. Another finding in this study is that early odontogenic marker genes such as Msx1, Msx2, Lhx7 and Pax9 were expressed in DSPP-overexpressed ADSCs. Thus, our results suggested that overexpression of DSPP promoted mineralization of ADSCs, and together with the expression of early odontogenic marker genes, implied that these cells may differentiate into functional odontoblast-like cells.
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PMID:Dentin sialophosphoprotein-promoted mineralization and expression of odontogenic genes in adipose-derived stromal cells. 1795 93

Although hypertension and vascular calcification are well established as important risk factors for several cardiovascular diseases, the relationship between them is unknown. Here, we investigated whether hypertension is relevant to vascular calcification by examining aortic smooth muscle cells (SMCs) isolated from the descending thoracic aortas of Wistar Kyoto rats (WKY) as normotensive rats and spontaneously hypertensive rats (SHR), a typical rat model of hypertension. Cells were cultured in DMEM containing 10% FBS for 6 days after reaching confluence. Von Kossa staining revealed that the positively stained calcified area of aortic SMCs from SHR increased rapidly compared to that from WKY. The gene expressions of calcification-regulating proteins including msh homeobox homolog 2, Osterix (a master transcription factor for osteogenesis), and alkaline phosphatase (ALP) (a marker of vascular calcification) were significantly increased in aortic SMCs from SHR compared to SMCs from WKY. On the other hand, Runx2, another osteogenic transcription factor, did not upregulate. Furthermore, we confirmed that ALP activity was strongly increased in aortic SMCs from SHR compared to SMCs from WKY. These results suggest that aortic SMCs from SHR tend to become easily calcified via an Msx2-Osterix signaling pathway.
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PMID:Calcification of aortic smooth muscle cells isolated from spontaneously hypertensive rats. 1827 Apr 71

Msx2 is a homeodomain transcription factor first identified in craniofacial bone and human femoral osteoblasts. We hypothesized that Msx2 might activate skeletal Wnt signaling. Therefore, we analyzed the effects of CMV-Msx2 transgene (Msx2Tg) expression on skeletal physiology and composition. Skeletal Msx2 expression was increased 2-3-fold by Msx2Tg, with expanded protein accumulation in marrow, secondary ossification centers, and periosteum. Microcomputed tomography established increased bone volume in Msx2Tg mice, with increased numbers of plate-like trabeculae. Histomorphometry revealed increased bone formation in Msx2Tg mice versus non-Tg siblings, arising from increased osteoblast numbers. While decreasing adipogenesis, Msx2Tg increased osteogenic differentiation via mechanisms inhibited by Dkk1, an antagonist of Wnt receptors LRP5 and LRP6. Bone from Msx2Tg mice elaborated higher levels of Wnt7 canonical agonists, with diminished Dkk1, changes that augment canonical signaling. Analysis of non-Tg and Msx2Tg siblings possessing the TOPGAL reporter confirmed this; Msx2Tg up-regulated skeletal beta-galactosidase expression (p </= 0.01), along with Wnt7a and Wnt7b, and reduced circulating Dkk1. To better understand molecular mechanisms, we studied C3H10T1/2 osteoprogenitor cells. As in bone, Msx2 increased Wnt7 genes and down-regulated Dkk1, while inducing the osteoblast gene alkaline phosphatase. Msx2-directed RNA interference increased Dkk1 expression and promoter activity, while reducing Wnt7a, Wnt7b, and alkaline phosphatase. Moreover, Msx2 inhibited Dkk1 promoter activity and reduced RNA polymerase association with Dkk1 chromatin. RNA interference-mediated knockdown of Wnt7a, Wnt7b, and LRP6 significantly reduced Msx2-induced alkaline phosphatase. Msx2 exerts bone anabolism in part by reducing Dkk1 expression and enhancing Wnt signaling, thus promoting osteogenic differentiation of skeletal progenitors.
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PMID:Msx2 exerts bone anabolism via canonical Wnt signaling. 1848 99

Several studies indicated that a homeobox gene, Msx2, is implicated in regulation of skeletal development by controlling enchondral ossification as well as membranous ossification. However, the molecular basis by which Msx2 conducts chondrogenesis is currently unclear. In this study, we examined the role of Msx2 in chondrocyte differentiation using mouse primary chondrocytes and embryonic metatarsal explants. Treatment with BMP2 up-regulated the expression of Msx2 mRNA along with chondrocyte differentiation in murine primary chondrocytes. Overexpression of wild-type Msx2 stimulated calcification of primary chondrocytes in the presence of BMP2. We also found that constitutively active Msx2 (caMsx2) enhanced BMP2-dependent calcification more efficiently than wild-type Msx2. Consistently, caMsx2 overexpression up-regulated the expression of alkaline phosphatase and collagen type X induced by BMP2. Furthermore, organ culture experiments using mouse embryonic metatarsals indicated that caMsx2 clearly stimulated the maturation of chondrocytes into the prehypertrophic and hypertrophic stages in the presence of BMP2. In contrast, knockdown of Msx2 inhibited maturation of primary chondrocytes. The stimulatory effect of Msx2 on chondrocyte maturation was enhanced by overexpression of Smad1 and Smad4 but inhibited by Smad6, an inhibitory Smad for BMP2 signaling. These data suggest that Msx2 requires BMP2/Smad signaling for its chondrogenic action. In addition, caMsx2 overexpression induced Ihh (Indian hedgehog) expression in mouse primary chondrocytes. Importantly, treatment with cyclopamine, a specific inhibitor for hedgehogs, blocked Msx2-induced chondrogenesis. Collectively, our results indicated that Msx2 promotes the maturation of chondrocytes, at least in part, through up-regulating Ihh expression.
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PMID:MSX2 stimulates chondrocyte maturation by controlling Ihh expression. 1868 98

Osterix/Sp7, a member of the Sp1 transcription factor family, plays an essential role in bone formation and osteoblastogenesis. Although Osterix has been shown to be induced by BMP2 in a mesenchymal cell line, the molecular basis of the regulation, expression and function of Osterix during osteoblast differentiation, is not fully understood. Thus we examined the role of BMP2 signaling in the regulation of Osterix using the mesenchymal cell lines C3H10T1/2 and C2C12. Osterix overexpression induced alkaline phosphatase activity and osteocalcin expression in C2C12 cells and stimulated calcification of murine primary osteoblasts. Considering that Runx2 overexpression induces Osterix, these results suggest that Osterix functions as downstream of Runx2. Surprisingly, BMP2 treatment induced Osterix expression and alkaline phosphatase activity in mesenchymal cells derived from Runx2-deficient mice. Furthermore, overexpression of Smad1 and Smad4 up-regulated Osterix expression, and an inhibitory Smad, Smad6, markedly suppressed BMP2-induced Osterix expression in the Runx2-deficient cells. Moreover, overexpression of a homeobox gene, Msx2, which is up-regulated by BMP2 and promotes osteoblastic differentiation, induced Osterix expression in the Runx2-deficient cells. Knockdown of Msx2 clearly inhibited induction of Osterix by BMP2 in the Runx2-deficient mesenchymal cells. Interestingly, microarray analyses using the Runx2-deficient cells revealed that the role of Osterix was distinct from that of Runx2. These findings suggest that Osterix is regulated via both Runx2-dependent and -independent mechanisms, and that Osterix controls osteoblast differentiation, at least in part, by regulating the expression of genes not controlled by Runx2.
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PMID:BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. 1870 12

Early changes of Runx2 and Msx2 expressions were examined by immunohistochemistry in mouse periodontal ligament exposed to mechanical stress. 8-week-old ddY mouse was used as experimental animal. To provide a continuous mechanical stress on periodontal ligament, rubber dam sheet was placed between upper molars of the mouse. At 20 minutes, 1 hour, 3 hours, 9 hours and 24 hours after insertion of the sheet, relevant parts of the mouse tissues were excised and fixed in 4% paraformaldehyde/0.05M phosphate buffered fixative solution. Then serial paraffin sections were prepared and histopathological evaluation as well as examination of Runx2, Msx2 and alkaline phosphatase (ALP) expressions by immunohistochemistry were performed. Control animals were not subjected to mechanical stress. In the experimental group, strong expressions of Runx2 and Msx2 were seen in periodontal fibroblasts of the tension side at 20 minutes after mechanical stress. Expressions of Runx2 and Msx2 became stronger in parallel with time, and at 24 hours after mechanical stress, the periodontal fibroblasts, cementoblasts as well as osteoblasts showed strong expression. Moreover, ALP has also demonstrated similar strong expression. On the other hand, in the control group, although expressions of Runx2, Msx2 and ALP were detected at all the experiment times, the expressions were weak. All these results strongly suggested that Runx2 promoted differentiation of osteoblasts at early stage and Msx2 worked as an activator of Runx2 function.
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PMID:Role of Msx2 as a promoting factor for Runx2 at the periodontal tension sides elicited by mechanical stress. 1894 34

T-box (Tbx)3, a known transcriptional repressor, is a member of a family of transcription factors, which contain a highly homologous DNA binding domain known as the Tbx domain. Based on the knowledge that mutation of the Tbx3 gene results in limb malformation, Tbx3 regulates osteoblast proliferation and its expression increases during osteoblast differentiation, we predicted that Tbx3 is an important regulator of osteoblast cell functions. In this study, we evaluated the consequence of transgenic overexpression of Tbx3 on osteoblast differentiation. Retroviral overexpression increased Tbx3 expression >100-fold at the mRNA and protein level. Overexpression of Tbx3 blocked mineralized nodule formation (28 +/- 8 vs. 7 +/- 1%) in MC3T3-E1 cells. In support of these data, alkaline phosphatase (ALP) activity was reduced 33-70% (P < 0.05) in both MC3T3-E1 cells and primary calvaria osteoblasts overexpressing Tbx3. In contrast, Tbx3 overexpression did not alter ALP activity in bone marrow stromal cells. Tbx3 overexpression blocked the increase in expression of key osteoblast marker genes, ALP, bone sialoprotein, and osteocalcin that occurs during normal osteoblast differentiation, but had little or no effect on expression of proliferation genes p53 and Myc. In addition, Tbx3 overexpression abolished increased osterix and runx2 expression observed during normal osteoblast differentiation, but the change in Msx1 and Msx2 expression over time was similar between control and Tbx3 overexpressing cells. Interestingly, osterix and runx2, but not Msx1 and Msx2, contain Tbx binding site in the regulatory region. Based on these data and our previous findings, we conclude that Tbx3 promotes proliferation and suppresses differentiation of osteoblasts and may be involved in regulating expression of key transcription factors involved in osteoblast differentiation.
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PMID:T-box 3 negatively regulates osteoblast differentiation by inhibiting expression of osterix and runx2. 1911 50

There were few studies investigating the effects of the mechanical stimulation provided by daily low-intensity pulsed ultrasound (LIPUS) treatment. LIPUS is known to accelerate bone mineralization and regeneration; however, the precise cellular mechanism is unclear.Our purpose was to determine how daily LIPUS treatment affected cell viability, alkaline phosphatase activity, osteogenesis-related gene expression, and mineralized nodule formation in osteoblasts. The typical osteoblastic cell line ROS 17/2.8 cells were cultured in the absence or presence of LIPUS stimulation. Daily LIPUS treatments (1.5 MHz; 20 min) were administered at an intensity of 30 mW/cm(2) for 14 days. Expression of osteogenesis-related genes was examined at mRNA levels using real-time polymerase chain reaction and at protein levels using western blotting analysis. LIPUS stimulation did not affect the rate of cell viability. Alkaline phosphatase activity was increased after 10 days of culture with daily LIPUS stimulation. LIPUS significantly increased the expression of mRNAs encoding Runx2, Msx2, Dlx5, osterix, bone sialoprotein, and bone morphogenetic protein-2, whereas it significantly reduced the expression of mRNA encoding the transcription factor AJ18. Mineralized nodule formation was markedly increased on Day 14 of LIPUS stimulation. LIPUS stimulation directly affected osteogenic cells, leading to mineralized nodule formation. LIPUS is likely to have a fundamental influence on key functional activities of osteoblasts in alveolar bone.
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PMID:Daily low-intensity pulsed ultrasound-mediated osteogenic differentiation in rat osteoblasts. 1920 27

The TWIST family of basic helix-loop-helix transcription factors, Twist-1 and Dermo-1 are known mediators of mesodermal tissue development and contribute to correct patterning of the skeleton. In this study, we demonstrate that freshly purified human bone marrow-derived mesenchymal stromal/stem cells (MSC) express high levels of Twist-1 and Dermo-1 which are downregulated following ex vivo expansion. Enforced expression of Twist-1 or Dermo-1 in human MSC cultures increased expression of the MSC marker, STRO-1, and the early osteogenic transcription factors, Runx2 and Msx2. Conversely, overexpression of Twist-1 and Dermo-1 was associated with a decrease in the gene expression of osteoblast-associated markers, bone morphogenic protein-2, bone sialoprotein, osteopontin, alkaline phosphatase and osteocalcin. High expressing Twist-1 or Dermo-1 MSC lines exhibited an enhanced proliferative potential of approximately 2.5-fold compared with control MSC populations that were associated with elevated levels of Id-1 and Id-2 gene expression. Functional studies demonstrated that high expressing Twist-1 and Dermo-1 MSC displayed a decreased capacity for osteo/chondrogenic differentiation and an enhanced capacity to undergo adipogenesis. These findings implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues by exerting their effects on genes involved in the early stages of bone development.
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PMID:TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. 1960 39

Bone marrow stromal cells (BMSCs) contain osteoprogenitors responsive to stimulation by osteogenic growth factors like bone morphogenetic proteins (BMPs). When used as grafts, BMSCs can be harvested from different skeletal sites such as axial, appendicular, and orofacial bones, but the lower therapeutic efficacy of BMPs on BMSCs-responsiveness in humans compared to animal models may be due partly to effects of skeletal site and age of donor. We previously reported superior differentiation capacity and osteogenic properties of orofacial BMSCs relative to iliac crest BMSCs in same individuals. This study tested the hypothesis that recombinant human BMP-2 (rhBMP-2) stimulates human BMSCs differently based on age and skeletal site of harvest. Adult maxilla, mandible, and iliac crest BMSCs from same individuals and pediatric iliac crest BMSCs were comparatively assessed for BMP-2 responsiveness under serum-containing and serum-free insulin-supplemented culture conditions. Adult orofacial BMSCs were more BMP-2-responsive than iliac crest BMSCs based on higher gene transcripts of alkaline phosphatase, osteopontin, and osteogenic transcription factors MSX-2 and Osterix in serum-free insulin-containing medium. Pediatric iliac crest BMSCs were more responsive to rhBMP-2 than adult iliac crest BMSCs based on higher expression of alkaline phosphatase and osteopontin in serum-containing medium. Unlike orofacial BMSCs, MSX-2 and Osterix transcripts were similarly expressed by adult and pediatric iliac crest BMSCs in response to rhBMP-2. These data demonstrate that age and skeletal site-specific differences exist in BMSC osteogenic responsiveness to BMP-2 stimulation and suggest that MSX-2 and Osterix may be potential regulatory transcription factors in BMP-mediated osteogenesis of adult orofacial cells.
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PMID:Age and skeletal sites affect BMP-2 responsiveness of human bone marrow stromal cells. 1963 63


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