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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic bone formation in the spinal ligaments. Mechanical stress, which acts on the posterior ligaments, is thought to be an important factor in the progression of OPLL. To clarify this mechanism, we investigated the effects of in vitro cyclic stretch (120% peak to peak, at 0.5 Hz) on cultured spinal ligament cells derived from OPLL (OPLL cells) and non-OPLL (non-OPLL cells) patients. The mRNA expressions of Cbfa1 (an osteoblast-specific transcription factor), type I collagen, alkaline phosphatase (ALP), osteocalcin and integrin beta1 (a mechanotransducer) were increased by cyclic stretch in OPLL cells, whereas no change was observed in non-OPLL cells. The effects of cyclic stretch on the spinal ligament tissues derived from OPLL and non-OPLL patients were also analyzed by immunohistochemistry using an antibody against Cbfa1. The expression of Cbfa1 was increased by cyclic stretch at the center of the spinal ligament tissues of OPLL patients, whereas no change was observed in the tissues of non-OPLL patients. Furthermore, U0126, a specific inhibitor of MAPK kinase (MEK), suppressed the stretch-induced mRNA expressions of Cbfa1, ALP and type I collagen in OPLL cells. These results suggest that in OPLL cells, mechanical stress is converted by integrin beta1 into intracellular signaling and that Cbfa1 is activated through the MAP kinase pathway. Therefore, we propose that mechanical stress plays a key role in the progression of OPLL through an increase in Cbfa1 expression.
...
PMID:Uni-axial cyclic stretch induces Cbfa1 expression in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament. 1463 70

It is well known that thyroid hormone modulates osteoblast cell function. We have previously shown that triiodothyronine (T(3)) activates p44/p42 mitogen-activated protein (MAP) kinase, which limits T(3)-induced alkaline phosphatase activity in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p44/p42 MAP kinase or p38 MAP kinase is involved in the thyroid hormone-stimulated osteocalcin synthesis in these cells. T(3) markedly induced the phosphorylation of p38 MAP kinase in addition to p44/p42 MAP kinase. PD98059 and U0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, had little effect on the T(3)-induced synthesis of osteocalcin. On the contrary, the T(3)-induced osteocalcin synthesis was significantly reduced by SB203580 and PD169316, inhibitors of p38 MAP kinase. SB203580, PD169316 or PD98059 suppressed the T(3)-phosphorylation of myelin basic protein. T(3)-induced osteocalcin synthesis was significantly reduced by SB203580 or PD169316 also in primary cultured mouse osteoblasts. These results strongly suggest that p38 MAP kinase but not p44/p42 MAP kinase takes part in the thyroid hormone-stimulated osteocalcin synthesis in osteoblasts.
...
PMID:Activation of p38 mitogen-activated protein kinase mediates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts. 1506 57

Parathyroid hormone-related protein (PTHrP) regulates proliferation and differentiation of osteoblastic cells via binding to the parathyroid hormone receptor (PTH-1R). The cAMP-dependent protein kinase A pathway governs the majority of these effects, but recent evidence also implicates the MAPK pathway. MC3T3-E1 subclone 4 cells (MC4) were treated with the MAPK inhibitor U0126 and PTHrP. In differentiated MC4 cells, osteocalcin and bone sialoprotein gene expression were both down-regulated by PTHrP and also by inhibition of the MAPK pathway. PTHrP-mediated down-regulation of PTH-1R mRNA and up-regulation of c-fos mRNA were MAPK-independent, whereas PTHrP stimulation of fra-2 and interleukin-6 (IL-6) mRNA was MAPK-dependent. Luciferase promoter assays revealed that regulation of IL-6 involved the cAMP-dependent protein kinase A and MAPK pathways with a potential minor role of the protein kinase C pathway, and a promoter region containing an activator protein-1 site was necessary for PTHrP-induced IL-6 gene transcription. An alternative pathway, through cAMP/Epac/Rap1/MAPK, mediated ERK phosphorylation but was not sufficient for IL-6 promoter activation. Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity. Most interesting, a bidirectional effect was found with PTHrP increasing phosphorylated ERK in undifferentiated MC4 cells but decreasing phosphorylated ERK in differentiated cells. These data indicate that inactivation of the MAPK pathway shows differential regulation of PTHrP-stimulated activator protein-1 members, blocks PTHrP-stimulated IL-6, and synergistically down-regulates certain osteoblastic markers associated with differentiation. These novel findings indicate that the MAPK pathway plays a selective but important role in the actions of PTHrP.
...
PMID:Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts. 1512 46

In the present in vitro study, we tested the hypothesis that parathyroid hormone-related protein (PTHrP) might be a mediator of interleukin-6 (IL-6) and its soluble receptor (IL-6sR) in osteoblasts. We found that IL-6, within 1-20 ng/mL, added together with IL-6sR (100 ng/mL), rapidly (1 hour) increased PTHrP mRNA in human osteoblastic osteosarcoma MG-63 cells and human osteoblastic (hOB) cells from trabecular bone. PD098059, a mitogen-activated protein kinase (MAPK) kinase inhibitor, at 10 microM, and two inhibitors of protein prenylation and thus Ras activation, simvastatin (1 microM) and a farnesyltransferase (FTase) inhibitor (100 nM), but not the phosphatidylinositol 3-kinase inhibitor wortmannin, blocked the IL-6/IL-6sR-induced PTHrP expression in these cells. In addition, PD098059 as well as simvastatin and the FTase inhibitor abolished alkaline phosphatase activity and/or osteocalcin mRNA induction by the IL-6/IL-6sR in these cells. Our results support the role of the Ras/MAPK pathway as a major mechanism in the modulation of both PTHrP expression and differentiation in human osteoblasts.
...
PMID:The interleukin-6/soluble interleukin-6 receptor system induces parathyroid hormone-related protein in human osteoblastic cells. 1512 68

Lysophosphatidic acid (LPA) is a locally produced bioactive phospholipid which is involved in tissue repair. The objective of this study was to determine whether dental pulp tissue also responds to the phospholipid. Effects of LPA on proliferation, differentiation, and mitogen-activated protein kinase (MAPK) signaling of dental pulp fibroblasts (DPF) were examined in vitro. We report that DPF express LPA receptors LPA1, LPA2, and LPA3 and respond to the ligand with increased mitogenic activity. Involvement of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH(2)-terminal kinase in LPA signaling could be demonstrated by use of specific inhibitors and detection of the phosphorylation status of the kinases. An increased mitogenic activity paralleled a decreased number of alkaline-phosphatase-positive cells and expression levels of dentin sialophosphoprotein and osteocalcin. Together, these results suggest that dental pulp fibroblasts can respond to LPA, a process that may play a role in pulp tissue repair.
...
PMID:Dental pulp fibroblasts contain target cells for lysophosphatidic Acid. 1515 58

Matrix extracellular phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) is a recently isolated RGD-containing matrix protein that acts as the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia. It is also highly expressed by osteoblasts and osteocytes. We examined the regulation of MEPE/OF45 mRNA expression in osteoblastic cells derived from high-density cultures of primary rat bone marrow stromal cells incubated with dexamethasone, beta-glycerophosphate, and ascorbic acid. The level of MEPE/OF45 mRNA in these cells was down-regulated by the addition of fibroblast growth factor 2 (FGF2) for 48 h. These effects were observed in a dose-dependent manner between 2 and 10 ng/mL. FGF2 also reduced the expression of osteocalcin mRNA in these cells. In contrast, bone sialoprotein mRNA expression was increased by FGF2, while alpha1(I) procollagen mRNA expression was not altered. Additionally, neither Runx2 and osterix mRNA expression nor cell proliferation were affected by the addition of FGF2 in these high-density cultures, indicating that regulation by FGF2 may not be dependent on these transcription factors or on the proliferation of cells. Experiments using actinomycin D indicated that FGF2 decreased the stability of the MEPE/OF45 mRNA. Moreover, inhibition of a specific mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) by PD98059 blocked FGF2-regulated MEPE/OF45 expressions, indicating that this regulation requires the MAPK pathway. These results suggest that MEPE/OF45 gene is one of the targets of FGF2 and may play an important role during bone formation and calcification.
...
PMID:Regulation of mRNA expression of matrix extracellular phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) by fibroblast growth factor 2 in cultures of rat bone marrow-derived osteoblastic cells. 1524 99

Glucocorticoids play important roles in cell growth and differentiation. In this study, we investigated the effect of application of dexamethasone (DEX) at the early stage of chondrogenesis using the prechondrogenic cell line, ATDC5, which differentiates into chondrocytes in the presence of insulin. When ATDC5 cells were cultured in the presence of DEX and insulin, DEX inhibited insulin-induced cellular condensation and subsequent cartilaginous nodule formation, and reduced proteoglycan synthesis and type II collagen expression dose-dependently. Pretreatment with 10(-8) M DEX for 1 day inhibited insulin-induced Akt phosphorylation, but not ERK1/2 phosphorylation, in ATDC5 cells. Treatment of ATDC5 cells with insulin for more than 2 days upregulated the levels of phosphatidylinositol 3-kinase (PI3K) subunit proteins, p85 and p110, and Akt, whereas the upregulation was inhibited in the presence of 10(-8) M DEX. In electrophoresis mobility shift assays (EMSAs), treatment with 10(-8) M DEX inhibited DNA binding of Runx2 during culture of ATDC5 cells with insulin. Reporter assays using osteocalcin promoter showed that DEX inhibited Runx2-dependent transcription dose-dependently. Adenoviral introduction of dominant-negative (dn)-Akt or dn-Runx2 into ATDC5 cells inhibited cellular condensation and reduced proteoglycan synthesis upon incubation with insulin, whereas adenoviral introduction of Akt or Runx2 prevented the inhibition of chondrogenesis by DEX. These findings indicate that DEX inhibits chondrogenesis of ATDC5 cells at the early stage by downregulating Akt phosphorylation as well as the protein levels of PI3K subunits and Akt, thereby suppressing PI3K-Akt signaling, and by inhibiting DNA binding of Runx2 and Runx2-dependent transcription.
...
PMID:Dexamethasone inhibits insulin-induced chondrogenesis of ATDC5 cells by preventing PI3K-Akt signaling and DNA binding of Runx2. 1536 63

Extracellular matrix proteins (ECMs) serve as both a structural support for cells and a dynamic biochemical network that directs cellular activities. ECM proteins such as those of the SIBLING family (small integrin-binding ligand glycoprotein) could possess inherent growth factor activity. In this study, we demonstrate that exon 5 of dentin matrix protein 3 (phosphophoryn (PP)), a non-collagenous dentin ECM protein and SIBLING protein family member, up-regulates osteoblast marker genes in primary human adult mesenchymal stem cells (hMSCs), a mouse osteoblastic cell line (MC3T3-E1), and a mouse fibroblastic cell line (NIH3T3). Quantitative real-time PCR technology was used to quantify gene expression levels of bone markers such as Runx2, Osx (Osterix), bone/liver/kidney Alp (alkaline phosphatase), Ocn (osteocalcin), and Bsp (bone sialoprotein) in response to recombinant PP and stably transfected PP. PP up-regulated Runx2, Osx, and Ocn gene expression. PP increased OCN protein production in hMSCs and MC3T3-E1. ALP activity and calcium deposition was increased by PP in hMSC. Furthermore, an alpha(v)beta(3) integrin-blocking antibody significantly inhibited recombinant PP-induced expression of Runx2 in hMSCs, suggesting that signaling by PP is mediated through the integrin pathway. PP was also shown to activate p38, ERK1/2, and JNK, three components of the MAPK pathway. These data demonstrate a novel signaling function for PP in cell differentiation beyond the hypothesized role of PP in biomineralization.
...
PMID:Phosphophoryn regulates the gene expression and differentiation of NIH3T3, MC3T3-E1, and human mesenchymal stem cells via the integrin/MAPK signaling pathway. 1537 33

There is a common mechanism for mechanotransduction in cells, regardless of the cell type. Integrins, interacting with their matrix/environment, mediate increases in intracellular Ca2+ levels and activate MAP kinase cascades to cause ERK1/2 phosphorylation. Phosphorylated ERK1/2 causes the activation of the AP-1 family of transcription factors that are necessary for the pro-growth response. The pro-bone growth response involves upregulation of the genes c-fos, IGF-1, cyclooxygenase, and osteocalcin. In osteocytes, increases in intracellular Ca2+ levels may additionally occur by extracellular Ca2+ influx through a stretch-activated ion channel. Each bone cell appears fine-tuned for the type of stimulus, with accessory mechanotransduction signaling pathways, such as calcineurin-mediated activation of the tissue-specific transcription factor NF-AT, adjusting the outcome of signaling in each case.
...
PMID:Molecular regulation of mechanotransduction. 1569 10

The survival of osteoblast cells is one of the determinants of the development of osteoporosis in patients. Osthole (7-methoxy-8-isopentenoxycoumarin) is a coumarin derivative present in many medicinal plants. By means of alkaline phosphatase (ALP) activity, osteocalcin, osteopontin, and type I collagen, enzyme-linked immunosorbent assay, we have shown that osthole exhibits a significant induction of differentiation in two human osteoblast-like cell lines, MG-63 and hFOB. Induction of differentiation by osthole was associated with increased bone morphogenetic protein (BMP)-2 production and the activations of SMAD1/5/8 and p38 and extracellular signal-regulated kinase (ERK) 1/2 kinases. Addition of purified BMP-2 protein did not increase the up-regulation of ALP activity and osteocalcin by osthole, whereas the BMP-2 antagonist noggin blocked both osthole and BMP-2-mediated ALP activity enhancement, indicating that BMP-2 production is required in osthole-mediated osteoblast maturation. Pretreatment of osteoblast cells with noggin abrogated p38 activation but only partially decreased ERK1/2 activation, suggesting that BMP-2 signaling is required in p38 activation and is partially involved in ERK1/2 activation in osthole-treated osteoblast cells. Cotreatment of p38 inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] or p38 small interfering RNA (siRNA) expression inhibited osthole-mediated activation of ALP but only slightly affected osteocalcin production. In contrast, the production of osteocalcin induced by osthole was inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 (2'-amino-3'-methoxyflavone) or by expression of an ERK2 siRNA. These data suggest that BMP-2/p38 pathway links to the early phase, whereas ERK1/2 pathway is associated with the later phase in osthole-mediated differentiation of osteoblast cells. In this study, we demonstrate that osthole is a promising agent for treating osteoporosis.
...
PMID:Osthole-mediated cell differentiation through bone morphogenetic protein-2/p38 and extracellular signal-regulated kinase 1/2 pathway in human osteoblast cells. 1595 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---