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)

Ca(2+)/calmodulin-dependent protein kinase IIalpha (alpha-CaMKII) was once thought to be exclusively expressed in neuronal tissue, but it is becoming increasingly evident that CaMKII is also expressed in various extraneural cells. CaMKII plays a critical role in regulating various signaling pathways leading to modulation of several aspects of cellular functions, including proliferation, differentiation, cytoskeletal structure, and gene expression. The purpose of this study was to examine the expression of CaMKII in osteoblast-like cells (MC4) and to elucidate its role in osteoblast differentiation. We demonstrated that CaMKII, specifically the alpha isoform, is expressed in osteoblasts both in vitro and in vivo. Inhibition of CaMKII by the calmodulin antagonist trifluoperazine or the CaMKII antagonist KN93 reduces alkaline phosphatase activity and mineralization, as well as causes 85 and 56% decreases in alkaline phosphatase and osteocalcin gene expression, respectively. CaM and CaMKII antagonists, using the newborn mouse calvaria in vivo model, cause a 50% decrease in osteoblast number (N.Ob-BS) and a 32% decrease in mineralization (BV/TV). Pharmacologic and genetic inhibition of alpha-CaMKII by using trifluoperazine, KN93, and alpha-CaMKII small interfering RNA decreases the phosphorylation of ERK and of cAMP-response element-binding protein, leading to a significant decrease in the transactivation of serum response element and cAMP-response element. Inhibition of alpha-CaMKII decreases the expression of c-fos, AP-1 transactivation, and AP-1 DNA binding activity. Our findings demonstrated that alpha-CaMKII is expressed in osteoblasts and is involved in c-fos expression via regulation of serum response element and cAMP-response element. Inhibition of alpha-CaMKII results in a decrease in c-fos expression and AP-1 activation, leading to inhibition of osteoblast differentiation.
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PMID:Calmodulin and calmodulin-dependent kinase IIalpha regulate osteoblast differentiation by controlling c-fos expression. 1559 Jun 32

Osteosarcoma is a malignant bone tumor that commonly affects adolescents and young adults. In the present study a human osteosarcoma cell line, KTHOS, was established from a primary osteosarcoma lesion in the distal femur of a 16-year-old girl. After 106 passages, the KTHOS cell line retained the biological characteristics of osteosarcoma. The KTHOS cells had spindle to pleomorphic cytoplasm with round to ovoid nuclei containing multiple prominent nucleoli, as expected based on the mesodermic origin of osteoblasts. The KTHOS cells were immunoreactive for osteocalcin, osteonectin, stem cell factor (SCF), and KIT (CD117). Reverse transcriptase-polymerase chain reaction indicated that the KTHOS cell line expressed mRNA for SCF and KIT. The KTHOS cells produced relatively high amounts of soluble SCF as determined by enzyme-linked immunosorbent assay. The results suggest that cell proliferation of the KTHOS cell line might be involved in autocrine and/or paracrine loops of the SCF/KIT signaling system. The KTHOS cell line is a novel human osteosarcoma cell line that releases SCF and expresses KIT. This cell line can be used for studies to explore the mechanisms for oncogenesis of human osteosarcomas.
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PMID:Establishment and characterization of a KIT-positive and stem cell factor-producing cell line, KTHOS, derived from human osteosarcoma. 1569 48

Prostate cancer frequently metastasizes to bone resulting in the formation of osteoblastic metastases through unknown mechanisms. Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity. Accordingly, we tested if VEGF contributes to the ability of prostate cancer to induce osteoblast activity. PC-3, LNCaP, and C4-2B prostate cancer cell lines expressed both VEGF-165 and VEGF-189 mRNA isoforms and VEGF protein. Prostate cancer cells expressed the mRNA for VEGF receptor (VEGFR) neuropilin-1 but not the VEGFRs Flt-1 or KDR. In contrast, mouse pre-osteoblastic cells (MC3T3-E1) expressed Flt-1 and neuropilin-1 mRNA but not KDR. PTK787, a VEGFR tyrosine kinase inhibitor, inhibited the proliferation of human microvascular endothelial cells but not prostate cancer proliferation in vitro. C4-2B conditioned medium induced osteoblast differentiation as measured by production of alkaline phosphatase and osteocalcin and mineralization of MC3T3-E1. PTK787 blocked the C4-2B conditioned medium-induced osteoblastic activity. VEGF directly induced alkaline phosphatase and osteocalcin but not mineralization of MC3T3-E1. These results suggest that VEGF induces initial differentiation of osteoblasts but requires other factors, present in C4-2B, to induce mineralization. To determine if VEGF influences the ability of prostate cancer to develop osteoblastic lesions, we injected C4-2B cells into the tibia of mice and, after the tumors grew for 6 weeks, administered PTK787 for 4 weeks. PTK787 decreased both intratibial tumor burden and C4-2B-induced osteoblastic activity as measured by bone mineral density and serum osteocalcin. These results show that VEGF contributes to prostate cancer-induced osteoblastic activity in vivo.
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PMID:Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. 1632 39

The aim of this study was to investigate the expression of osteocalcin (OCN) splicing variants in hematological malignancies. We analysed bone marrow obtained from two patients with chronic myeloid leukemia (CML), seven patients with other myeloproliferative diseases (MPD) and four patients with acute myeloid leukemia (AML). RT-PCR analyses were performed in order to assess and quantify spliced (OCNs) and unspliced (OCNu) mRNA, the associated transcription factors (AML1 and AML3) as well as c-KIT which is a marker for activated stem cells. Our data indicate that OCNs mRNA and OCN protein is expressed in c-KIT positive neoplastic stem cells in hematological malignancies.
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PMID:Expression and functional significance of osteocalcin splicing in disease progression of hematological malignancies. 1638 59

Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies. The expression patterns of IHH (Indian hedgehog) and FGFR3 (Fibroblast Growth Factor Receptor 3) were similar with transcripts expressed throughout osteochondromas. Expression of PTHR1 (Parathyroid Hormone Receptor 1) transcripts was restricted to a narrow zone of prehypertrophic chondrocytes. Numerous cells forming osteochondromas although resembling prehypertrophic chondrocytes, stained positively with an anti-proliferating cell nuclear antigen (PCNA) antibody. In addition, ectopic expression of collagen type I and abnormal presence of osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP) were observed in the cartilaginous osteochondromas. These data indicate that most chondrocytes involved in the growth of osteochondromas can proliferate, and that some of them exhibit bone-forming cell characteristics. We conclude that in MHE, defective heparan sulfate biosynthesis caused by EXT mutations maintains the proliferative capacity of chondrocytes and promotes phenotypic modification to bone-forming cells.
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PMID:Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients. 1647 76

The osteogenic potential of mesenchymal stem cells (MSCs) cultured on poly(lactide-co-glycolide) (PLGA) or poly(caprolactone) (PCL), two widely used polymeric biomaterials that have been reported to differentially support osteogenic differentiation, was compared in these studies. Here we report that MSCs cultured in 3-D PLGA scaffolds for up to 5 weeks significantly upregulate osteocalcin gene expression levels. By contrast, osteocalcin expression was markedly downregulated in 3-D PCL-based constructs over the same time course. We hypothesized that differential adsorption of extracellular matrix (ECM) proteins present in serum-containing culture medium and subsequent differences in integrin-mediated adhesion are responsible for these differences, and tested this hypothesis using thin (2-D) polymeric films. Supporting this hypothesis, significant amounts of fibronectin and vitronectin deposited onto both materials in serum-containing osteogenic media, with type-I collagen present in lower amounts. Adhesion-blocking studies revealed that MSCs adhere to PCL primarily via vitronectin, while type-I collagen mediates their attachment to PLGA. These adhesive mechanisms correlated with higher levels of alkaline phosphatase (ALP) activity after 2 weeks of monolayer culture on PLGA versus PCL. These data suggest that the initial adhesion of MSCs to PLGA via type-I collagen fosters osteogenesis while adhesion to PCL via vitronectin does not, and stress the need for an improved molecular understanding of cell-ECM interactions in stem cell-based therapies.
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PMID:Adhesion of mesenchymal stem cells to polymer scaffolds occurs via distinct ECM ligands and controls their osteogenic differentiation. 1660 24

The process of vascular calcification presents several features similar to osteogenesis in which fibronectin (FN) acts as a regulator of osteoblastic differentiation and the ERK signal pathway is involved. In order to find whether FN promotes the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the ERK signal pathway, we investigated the effect of FN on the calcification of VSMCs by using an in vitro cell model. VSMCs cultured in plates with FN (0-20 microg/cm2) coating were induced to calcify by 10 mM sodium beta-glycerophosphate (beta-GP). FN exacerbated VSMC calcification in a dose- and time-dependent manner, as indicated by the number of calcifying nodules per slide and the amount of calcium in the deposition. Data from RT-PCR and immunoblotting assay revealed that FN also enhanced the expression of several phenotypic markers of osteoblasts, including alkaline phosphatase (ALP) activity, osteocalcin (OC), and Osf2/Cbfa1, a key transcription factor in osteoblastic differentiation. Furthermore, a specific inhibitor for ERK, PD98059 (10 microM), significantly suppressed the effect of FN on calcification and phenotypic marker expression. These findings seem to suggest that FN enhanced vascular calcification by promoting the osteoblastic differentiation of VSMCs via ERK signal pathway.
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PMID:Fibronectin enhances in vitro vascular calcification by promoting osteoblastic differentiation of vascular smooth muscle cells via ERK pathway. 1679 48

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

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

Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family and has been implicated in embryonic development, differentiation, inflammation, and regeneration of liver and bone. In the present study, we demonstrated that treatment of human adipose mesenchymal stem cells (hADSCs) with OSM-attenuated adipogenic differentiation, as indicated by decreased accumulation of intracellular lipid droplets and down-regulated expression of adipocytic markers, such as lipoprotein lipase and PPARgamma. However, OSM treatment stimulated osteogenic differentiation, as demonstrated by the increase in matrix mineralization and expression levels of osteogenic differentiation markers, including alkaline phosphatase, Runx2, and osteocalcin. OSM treatment induced activation of JAK2, JAK3, and ERK in hADSCs, and pre-treatment of hADSCs with the JAK2 inhibitor, AG490, significantly restored the OSM-induced inhibition of adipogenic differentiation. Whereas, the JAK3 inhibitor, WHI-P131, and the MEK inhibitor, U0126, had no effects on the anti-adipogenic activity of OSM. On the other hand, the pro-osteogenic activity of OSM was prevented by treatment of the cells with WHI-P131 or U0126, but not with AG490. These results indicate that distinct signaling pathways, including JAK2, JAK3, and MEK-ERK, play specific roles in the OSM-induced anti-adipogenic and pro-osteogenic differentiation of hADSCs.
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PMID:Oncostatin M promotes osteogenesis and suppresses adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells. 1722 68


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