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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(epsilon-caprolactone) (PCL) film was modified using specified amounts of poly(d,l-lactide-co-glycolide) (PLGA) to provide a means to control polymer degradation. The aim of the study was to determine the effects of doping PCL with PLGA on the materials degradation, morphology and cell adhesion, to determine the significant variables within the process that could provide further control of cell adhesion. PLGA-doped PCL films were aged in osteogenic medium at 37 degrees C for up to 28 days. The aged samples were analysed in terms of weight loss or weight gain, molecule deposition and surface morphology. Molecule deposition was determined using Fourier transform infrared spectroscopy in attenuated total reflectance mode (FTIR-ATR) and morphology was determined using scanning electron microscopy and interferometric microscopy. The loss of the PLGA doping during degradation enhanced the formation of nano-porous structures in the remaining PCL domains, which attracted the deposition of substances from the osteogenic medium, which favoured the attachment and growth of human osteoblasts. The growth of osteoblasts was influenced by the controlled release of acidic products through polymer blending. Two pairs of FTIR-ATR absorption bands at 1090 and 1110 cm(-1), and at 1180 and 1190 cm(-1) were found to correlate to both PLGA and PCL, respectively. Changing the level of PLGA doping in PCL provided an approach to control the acidic products which can direct the growth of osteoblast cells.
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PMID:The effect of PLGA doping of polycaprolactone films on the control of osteoblast adhesion and proliferation in vitro. 1667 5

Mutations in fibroblast growth factor receptors (Fgfrs) 1-3 cause skeletal disease syndromes in humans. Although these Fgfrs are expressed at various stages of chondrocyte and osteoblast development, their function in specific skeletal cell types is poorly understood. Using conditional inactivation of Fgfr1 in osteo-chondrocyte progenitor cells and in differentiated osteoblasts, we provide evidence that FGFR1 signaling is important for different stages of osteoblast maturation. Examination of osteogenic markers showed that inactivation of FGFR1 in osteo-chondro-progenitor cells delayed osteoblast differentiation, but that inactivation of FGFR1 in differentiated osteoblasts accelerated differentiation. In vitro osteoblast cultures recapitulated the in vivo effect of FGFR1 on stage-specific osteoblast maturation. In immature osteoblasts, FGFR1 deficiency increased proliferation and delayed differentiation and matrix mineralization, whereas in differentiated osteoblasts, FGFR1 deficiency enhanced mineralization. Furthermore, FGFR1 deficiency in differentiated osteoblasts resulted in increased expression of Fgfr3, a molecule that regulates the activity of differentiated osteoblasts. Mice lacking Fgfr1, either in progenitor cells or in differentiated osteoblasts, showed increased bone mass as adults. These data demonstrate that signaling through FGFR1 in osteoblasts is necessary to maintain the balance between bone formation and remodeling through a direct effect on osteoblast maturation.
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PMID:Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. 1681 85

Fibroblast growth factor-2 (FGF2) is a powerful promoter of bone growth. We demonstrate here that brief exposure to FGF2 enhances mineralized nodule formation in cultured rat osteoprogenitor cells due to an expansion of cells that subsequently mineralize. This mitogenic effect is mediated via sulfated glycosaminoglycans (GAGs), FGFR1, and the extracellular signal-regulated kinase (ERK) pathway. The GAGs involved in this stimulation are chondroitin sulfates (CS) rather than heparan sulfates (HS). However, continuous FGF2 treatment reduces alkaline phosphatase (ALP) activity, downregulates collagen Ialpha1 (ColIalpha1) and FGFR3 expression, upregulates the expression and secretion of osteopontin (OPN) and inhibits mineralization. The inhibitory effects of FGF2 on FGFR3 expression and ALP activity are also mediated by the ERK pathway, although the effects of FGF2 on ColIalpha1 and OPN expression are mediated by GAGs and PKC activity. Thus short-term activation of FGF2/FGFR1 promotes osteoprogenitor proliferation and subsequent differentiation, while long-term activation of FGF2 signaling disrupts mineralization by modulating osteogenic marker expression. This study thus establishes the central role of sulfated GAGs in the osteogenic progression of osteoprogenitors.
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PMID:Sulfated glycosaminoglycans mediate the effects of FGF2 on the osteogenic potential of rat calvarial osteoprogenitor cells. 1697 47

Bone tissue homeostasis relies upon the ability of cells to detect and interpret extracellular signals that direct changes in tissue architecture. This study utilized a four-point bending model to create both fluid shear and strain forces (loading) during the time-dependent progression of MC3T3-E1 preosteoblasts along the osteogenic lineage. Loading was shown to increase cell number, alkaline phosphatase (ALP) activity, collagen synthesis, and the mRNA expression levels of Runx2, osteocalcin (OC), osteopontin, and cyclo-oxygenase-2. However, mineralization in these cultures was inhibited, despite an increase in calcium accumulation, suggesting that loading may inhibit mineralization in order to increase matrix deposition. Loading also increased fibroblast growth factor receptor-3 (FGFR3) expression coincident with an inhibition of FGFR1, FGFR4, FGF1, and extracellular signal-related kinase (ERK)1/2 phosphorylation. To examine whether these loading-induced changes in cell phenotype and FGFR expression could be attributed to the inhibition of ERK1/2 phosphorylation, cells were grown for 25 days in the presence of the MEK1/2 inhibitor, U0126. Significant increases in the expression of FGFR3, ALP, and OC were observed, as well as the inhibition of FGFR1, FGFR4, and FGF1. However, U0126 also increased matrix mineralization, demonstrating that inhibition of ERK1/2 phosphorylation cannot fully account for the changes observed in response to loading. In conclusion, this study demonstrates that preosteoblasts are mechanoresponsive, and that long-term loading, whilst increasing proliferation and differentiation of preosteoblasts, inhibits matrix mineralization. In addition, the increase in FGFR3 expression suggests that it may have a role in osteoblast differentiation.
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PMID:Long-term loading inhibits ERK1/2 phosphorylation and increases FGFR3 expression in MC3T3-E1 osteoblast cells. 1697 71

Flavonoids, which have been detected in a variety of foods, have been repeatedly reported to affect bone metabolism. However, the effects of flavonoids on osteoblastogenesis remain a matter of some controversy. In this study, the effects of quercetin on the differentiation and proliferation of human adipose tissue-derived stromal cells (hADSC) were determined. Quercetin was found to increase osteogenic differentiation in a dose-dependent manner. Other flavonoids, chrysin and kaempferol, were also shown to increase the osteogenic differentiation of hADSC, but this stimulatory effect was weaker than that associated with quercetin. Quercetin pretreatment administered prior to the induction of differentiation also exerted stimulatory effects on the osteogenic differentiation of hADSC. RT-PCR and real time PCR analysis showed that quercetin treatment induced an increase in the expression of osteopontin, BMP2, alkaline phosphatase and Runx2. Quercetin inhibited the proliferation of hADSC, but did not affect their survival. The pretreatment of quercetin increased ERK phosphorylation during osteogenic differentiation, although it did not increase ERK activity in control culture condition. ICI182780, an specific estrogen receptor antagonist, failed to inhibit the effects of quercetin on osteogenic differentiation. Quercetin-pretreated hADSC showed better bone regenerating ability in skull defect model of nude mice than naive cells. Our findings indicate that quercetin enhances osteogenic differentiation via an independent mechanism from estrogen receptor (ER) activation, and prove useful for in vivo bone engineering, using human mesencymal stem cells (hMSC).
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PMID:Quercetin, a flavonoid, inhibits proliferation and increases osteogenic differentiation in human adipose stromal cells. 1699 34

The study of MS-KIF18A kinesin protein is focused on its cellular distribution and association with a cargo protein. Indirect immunofluorescence (IF) analyzed the intracellular distribution of endogenous MS-KIF18A and the transfected enhanced green fluorescence protein (eGFP)-MS-KIF18A in osteogenic cells. In both cases, the proteins were localized at the plasma membrane, cytosol, and nucleus. Bioinformatics analysis suggested interactions between MS-KIF18A and estrogen receptor (ERalpha) which were further elucidated by immunoprecipitation (IP). We identified interaction between endogenous MS-KIF18A with 66 and 46 kDa isoforms of ERalpha in MBA-15 cells. Moreover, MS-KIF18A and 66 kDa ERalpha complex has been demonstrated between ectopically expressed proteins in COS-7 cells. We have shown that anti-MS-KIF18A antibody immunoprecipitated the ERalpha and pERK in cells challenged with 17beta-estrogen (17beta-E2). The hormone activation induced mitogen-activated protein kinases (MAPK) pathway and increased p-ERK. The activation was interfered when cells were pre-treated with either ICI-182,780 or MAPK inhibitor PD98059 prior the challenge with 17beta-E2 that resulted in a decrease in association between MS-KIF18A and p-ERK1/2. The obtained results suggest a role for the proteins in a non-genomic response of MBA-15 cells challenged with 17beta-E2. This study presents a novel interaction between MS-KIF18A and ER that may have important physiological and pharmacological implications for estrogen action in various cells.
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PMID:MS-KIF18A, a kinesin, is associated with estrogen receptor. 1700 58

The intracellular signaling events controlling human mesenchymal stem cells (hMSC) differentiation into osteoblasts are not entirely understood. We recently demonstrated that contact with extracellular matrix (ECM) proteins is sufficient to induce osteogenic differentiation of hMSC through an ERK-dependent pathway. We hypothesized that FAK signaling pathways provide a link between activation of ERK1/2 by ECM, and stimulate subsequent phosphorylation of the Runx2/Cbfa-1 transcription factor that controls osteogenic gene expression. We plated hMSC on purified collagen I (COLL-I) and vitronectin (VN) in the presence or absence of FAK-specific siRNA, and assayed for phosphorylation of Runx2/Cbfa-1 as well as expression of established osteogenic differentiation markers (bone sialoprotein-2, osteocalcin, alkaline phosphatase, calcium deposition, and spectroscopically determined mineral:matrix ratio). We found that siRNA treatment reduced FAK mRNA levels by >40% and decreased ECM-mediated phosphorylation of FAK Y397 and ERK1/2. Serine phosphorylation of Runx2/Cbfa-1 was significantly reduced after 8 days in treated cells. Finally, FAK inhibition blocked osterix transcriptional activity and the osteogenic differentiation of hMSC, as assessed by lowered expression of osteogenic genes (RT-PCR), decreased alkaline phosphatase activity, greatly reduced calcium deposition, and a lower mineral:matrix ratio after 28 days in culture. These results suggest that FAK signaling plays an important role in regulating ECM-induced osteogenic differentiation of hMSC.
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PMID:Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells. 1708 17

Mesenchymal stem cells (MSCs) can differentiate into diverse cell types including adipogenic, osteogenic, chondrogenic and myogenic lineages. In the present study, we demonstrated for the first time that sphingosylphosphorylcholine (SPC) induces differentiation of human adipose-tissue-derived mesenchymal stem cells (hATSCs) to smooth-muscle-like cell types. SPC increased the expression levels of several smooth-muscle-specific genes, such as those for alpha-smooth-muscle actin (alpha-SMA), h1-calponin and SM22alpha, as effectively as transforming growth factor beta (TGF-beta1) and TGF-beta3. SPC elicited delayed phosphorylation of Smad2 after 24 hours exposure, in contrast to rapid phosphorylation of Smad2 induced by TGF-beta treatment for 10 minutes. Pretreatment of the cells with pertussis toxin or U0126, an MEK inhibitor, markedly attenuated the SPC-induced expression of beta-SMA and delayed phosphorylation of Smad2, suggesting that the Gi/o-ERK pathway is involved in the increased expression of alpha-SMA through induction of delayed Smad2 activation. In addition, SPC increased secretion of TGF-beta1 through an ERK-dependent pathway, and the SPC-induced expression of alpha-SMA and delayed phosphorylation of Smad2 were blocked by SB-431542, a TGF-beta type I receptor kinase inhibitor, or anti-TGF-beta1 neutralizing antibody. Silencing of Smad2 expression with small interfering RNA (siRNA) abrogated the SPC-induced expression of alpha-SMA. These results suggest that SPC-stimulated secretion of TGF-beta1 plays a crucial role in SPC-induced smooth muscle cell (SMC) differentiation through a Smad2-dependent pathway. Both SPC and TGF-beta increased the expression levels of serum-response factor (SRF) and myocardin, transcription factors involved in smooth muscle differentiation. siRNA-mediated depletion of SRF or myocardin abolished the alpha-SMA expression induced by SPC or TGF-beta. These results suggest that SPC induces differentiation of hATSCs to smooth-muscle-like cell types through G(i/o)-ERK-dependent autocrine secretion of TGF-beta, which activates a Smad2-SRF/myocardin-dependent pathway.
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PMID:Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-beta-dependent mechanism. 1710 65

Several features of the implant surface, such as roughness, topography and composition play a relevant role in implant integration with bone. This study was conducted in order to determine the effects of various thin layer hydroxyapatite (HA) coatings on anodized Ti surfaces on the biological responses of a human osteoblast-like cell line (MG63). MG63 cells were cultured on 100 nm HA (100 nm HA coating on anodized surface), 500-700 nm HA (500-700 nm HA coating on anodized surface), 1 mum HA (1 mum HA coating on anodized surface) and anodize (non-HA coating on anodized surface) Ti. The morphology of these cells was assessed by scanning electron microscopy (SEM). The cDNAs prepared from the total RNAs of the MG63 were hybridized into a human cDNA microarray (1152 elements). The appearances of the surfaces observed by SEM were different on each of the four dental substrate types. MG63 cells cultured on 100 nm HA, 1 mum HA and anodize exhibited cell-matrix interactions. It was 500-700 nm HA surface showing cell-cell interaction. In the expression of genes involved in osseointegration, several genes, including bone morphogenetic protein 2, latent transforming growth factor beta binding protein 1, catenin (cadherin-associated protein), integrin, PDGFRB and GDF-1 growth differentiation factor 1 were up-regulated on the different surfaces. Several genes, including fibroblast growth factor receptor 3, fibroblast growth factor 12 and CD4 were down-regulated on the different surfaces. The attachment and expression of key osteogenic regulatory genes were enhanced by the surface morphology of the dental materials used.
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PMID:Biological responses in osteoblast-like cell line according to thin layer hydroxyapatite coatings on anodized titanium. 1716 32

Tissue stem cells may serve as progenitors for malignant tumors derived from the same tissue. Here, we report the establishment of immortalized human mesenchymal stem cells (ihMSC) and tested the feasibility of using ihMSC as presarcomatous cells. Immortalization was achieved by introducing the genes for human telomerase reverse transcriptase and Bmi1. ihMSC retained the potential for multi-directional differentiation of the original MSC. To transform ihMSC, we introduced an oncogenic H-ras(Val12) gene, and established the cell line ihMSC-ras. ihMSC-ras had the phenotype of fully transformed cells and retained adipogenic and chondrogenic, but not osteogenic, potential. Interestingly, ihMSC-ras demonstrated morphological features of autophagy, and inhibition of the ERK pathway suppressed the production of autophagosomes, indicating that ras/ERK signaling is responsible for the induction of autophagy. Thus ihMSC will serve as a material with which to analyze the tumorigenic and differentiation-modifying effects of candidate oncogenes involved in the development of sarcomas.
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PMID:In vitro transformation of mesenchymal stem cells by oncogenic H-rasVal12. 1717 60


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