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At least 163 records · Page 9Linked to original sources
PubMed1997

Activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) by FGF-2 and PDGF-BB in normal human osteoblastic and bone marrow stromal cells: differences in mobility and in-gel renaturation of ERK1 in human, rat, and mouse osteoblastic cells.

We recently demonstrated that basic fibroblast growth factor (FGF-2) and platelet-derived growth factor-BB (PDGF-BB) mainly activated extracellular signal-regulated kinase 2 (ERK2) in normal human osteoblastic (HOB) and bone marrow stromal (HBMS) cells by an "in-gel" MAP kinase assay, although both ERK1 and ERK2 proteins were present. In the present study, we examined whether ERK1 is also activated by growth factors by using three different MAPK assay procedures, an "in-gel MAP kinase assay," an immune-complex kinase assay, and western blotting with anti-active MAPK antibody which recognizes specifically activated forms of both ERK1 and ERK2. Results have demonstrated that in addition to ERK2, ERK1 is activated by FGF-2 and PDGF-BB in normal HOB and HBMS cells. The human ERK1 moved faster on SDS-polyacrylamide gel compared to rat and mouse, revealing differences in the apparent molecular weight of FRK1 in normal human osteoblastic and bone marrow osteoprogenitor cells, human (TE-85) and rat (ROS 17/2.8 and UMR-106) osteosarcoma, and mouse (MC3T3E1) osteoblastic cells. ERK1 is less stable in the in-gel renaturation process compared to ERK2; thus, in-gel MAP kinase assay does not provide an accurate estimation of ERK1 activity. Results also showed that anti-active MAPK antibody can be used reliably and accurately to measure the activation of ERK1 and ERK2 in osteoblastic cells.

Animals↗
PubMed1998

Platelet-derived growth factor (PDGF)-BB stimulates osteoclastic bone resorption directly: the role of receptor beta.

The growth-promoting activity of PDGF-BB was studied on the adult osteoclasts in the present study. The PDGF receptor beta was detected on the osteoclast membrane through immunohistochemistry (LSAB method) and immunomicroscopy. The PDGF-BB was exerted on the osteoclasts that adhered to the bone slice at concentrations of 0, 10, 20, 30, and 40 ng/ml. The volume of Howship's lacuna augmented significantly and the number of resorption pits also increased with its dose (p < 0.01). The activity of both total acid phosphatase (ACP) and tartrate-resistant acid phosphatase (TRAP) increased significantly. These results suggest that PDGF-BB promotes adult osteoclastic bone resorption directly through PDGF receptor beta and is believed to play important roles in the bone healing process and reconstruction.

Acid Phosphatase↗
PubMed1998

Upregulated expression of fibroblast growth factor (FGF) receptors by transforming growth factor-beta1 (TGF-beta1) mediates enhanced mitogenic responses to FGFs in cultured human lung fibroblasts.

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that induces mesenchymal cell proliferation in vivo while inhibiting growth of most cells directly via serine-threonine receptor(s) binding/activation in vitro. In this study, the ability of TGF-beta1 to regulate the receptor expression of classical mitogenic growth factors that bind receptor tyrosine kinases was examined. TGF-beta1 markedly increased the protein expression of the fibroblast growth factor (FGF) receptors FGFR-1 (Flg) and FGFR-2 (Bek) in a time- and dose-dependent manner in human lung fibroblasts. This resulted in a potentiation of the mitogenic response of multiple FGF ligands that bind to these receptors. TGF-beta1 had no effect on epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)-beta receptor expression and the mitogenic responses mediated by specific ligands for these receptors were not increased. These results demonstrate a novel action of TGF-beta1 to selectively upregulate the expression of FGF receptor family members leading to enhanced mitogenesis by FGFs.

Animals↗
PubMed1998

Protein kinase C phosphorylates and activates GTP cyclohydrolase I in rat renal mesangial cells.

GTP cyclohydrolase I is the rate-limiting enzyme in the de novo synthesis pathway of tetrahydrobiopterin which is an essential cofactor for all NO synthase isoforms. The expression of GTP cyclohydrolase I is regulated on a transcriptional level by a variety of cytokines like interleukin 1beta or tumor necrosis factor alpha. The present paper reports that stimulation of protein kinase C by angiotensin II, platelet-derived growth factor BB or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate triggers the phosphorylation and activation of GTP cyclohydrolase I. These data establish that in addition to transcriptional regulation, there is a prominent post-transcriptional modulation of enzyme activity.

Angiotensin II↗
PubMed1998

Collagen type I modulates the platelet-derived growth factor (PDGF) regulation of the growth and expression of beta1 integrins by rat mesangial cells.

Mesangial cell (MC) proliferation and the deposition of collagen type I (collagen I) are the major pathological features in many types of glomerulonephritis (GN). Recent work suggested that beta-integrins play a critical role in the cell proliferation and extracellular matrix (ECM) remodeling observed in tissue repair after injury. To examine the involvement of beta-integrins in MC proliferation in association with the interaction of MCs with pathological collagen I, we investigated the effect of a prominent mitogen, platelet-derived growth factor-BB (PDGF-BB) on the growth and expression of beta-integrins by MCs cultured on plastic or in a three-dimensional collagen I gel. Immunoprecipitation using 35S-metabolic labeling, flow cytometry and a 3H-thymidine-uptake analysis demonstrated that PDGF-BB stimulated the cell mitogenicity and the expression of alpha5beta1 integrin (a fibronectin receptor), but not alpha1beta1 integrin (a collagen and laminin receptor) of MCs on plastic, in a dose-dependent manner. In contrast, MCs in the collagen I gels showed no significant changes in mitogenicity or alpha1beta1 and alpha5beta1 integrin expression, but increased alpha1beta1 integrin-mediated gel contraction was observed after PDGF-BB stimulation. Thus, the parallel up-regulation of MC-mitogenicity and alpha5beta1 integrin expression by PDGF-BB suggested that alpha5beta1 integrin is an important ECM receptor involved in the proliferative phenotype of MC. A spatial interaction between MCs and pathological collagen I in GN may influence the PDGF regulation of the MC phenotype regarding the cell growth and the expression of beta1 integrins.

Animals↗
PubMed1999

The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor.

Evidence suggests that human cytomegalovirus (HCMV) infection contributes to the development of atherosclerosis and restenosis. Because smooth muscle cell (SMC) proliferation and migration are crucial events of both processes, and because PDGF beta-receptor modulates SMC migration, we determined whether HCMV infection affects SMC proliferation, migration, and PDGF beta-receptor expression. We employed a SMC model in which HCMV infection leads to expression of only the immediate early (IE) HCMV gene products-HCMV infection of rat SMCs. We found that HCMV infection significantly (i) increased SMC proliferation (from 0.9 x 10(6) +/- 0.024 x 10(6) to 1.4 x 10(6) +/- 0.051 x 10(6) cells/well, p < 0.001); (ii) augmented SMC migration toward PDGF (from 64 +/- 37 to 116 +/- 51 cells/high power field; p < 0.01); and (iii) enhanced PDGF beta-receptor expression in a time-dependent fashion. We conclude that HCMV infection of rat SMCs increases SMC proliferation, migration, and PDGF beta-receptor expression. These findings identify further mechanisms by which CMV may contribute to the development of atherosclerosis and restenosis.

Animals↗
PubMed1999

Platelet surface membranes are highly mitogenic for coronary artery smooth muscle cells--A novel mechanism for sustained proliferation after vessel injury?

The effects of isolated platelet surface membranes on DNA synthesis and proliferation of bovine coronary artery smooth muscle cells (SMC) were studied. Platelet membranes were very potent mitogens for SMC. The potency was about 10-fold higher than the maximum effects of platelet-derived growth factor-BB (PDGF). Platelet membrane-induced mitogenesis was inhibited by rapamycin, wortmannin or heating for 15 min at 70 degrees C but not by the PDGF receptor antagonist SCH 13.929 or by neutralizing PDGF antibodies. Only a partial (30%) inhibition was seen with PD 98059. In contrast, PDGF-induced SMC mitogenesis was heat-stable but sensitive to SCH 13. 929, PDGF antibodies, and PD 98059. These findings provide evidence for a novel mechanism for platelet-induced SMC proliferation that is independent of PDGF secretion. Platelet membranes, attached to or incorporated into the vessel wall, could maintain sustained SMC proliferation following injury.

Androstadienes↗
PubMed1999

An aldose reductase inhibitor prevents the glucose-induced increase in PDGF-beta receptor in cultured rat aortic smooth muscle cells.

To examine the role of platelet-derived growth factor (PDGF) and the polyol pathway in the growth activity of smooth muscle cells (SMCs), [(3)H]-thymidine incorporation, [(125)I]-PDGF-BB binding and expression of PDGF-beta receptor protein were measured in rat aortic SMCs cultured with 5.5 or 20 mM glucose with or without anti-PDGF antibody or an aldose reductase inhibitor, epalrestat. SMCs cultured with 20 mM glucose demonstrated an accelerated thymidine incorporation compared with SMCs cultured with 5.5 mM glucose, which was prevented by anti-PDGF antibody. This acceleration of growth activity by 20 mM glucose was accompanied by an increase in PDGF-BB binding, which was due to the increased number of PDGF-beta receptors and the overexpression of PDGF-beta receptor protein. Epalrestat prevented all these abnormalities. These observations suggest that polyol pathway hyperactivity plays an important role in the proliferation of SMCs which may be mediated through the accelerated expression of PDGF-beta receptor protein.

Aldehyde Reductase↗
PubMed2000

Growth hormones reverse desensitization of P2Y(2) receptors in rat mesangial cells.

Rat glomerular mesangial cells (GMC) express P2Y(2) purinoceptors and respond to nucleotide stimuli with a transient increase in the cytosolic Ca(2+) concentration and the receptors desensitize upon repeated stimulation with nucleotide. We demonstrate that there is a cross-talk from the signaling of tyrosine kinase to P2Y(2) receptors. For most cells repeated applications of ATP completely abolished the response, as did activation of PKC with 500 nM PMA. In contrast, preincubation with the PKC inhibitor chelerythrine (100 nM) prevented desensitization. Desensitization after application of ATP was reversed by subsequent incubation with PDGF-BB (50 ng/ml) or insulin (660 mU/ml). We conclude that the desensitization is caused by phosphorylation due to PKC and is under the control of growth factors. The findings support the hypothesis that growth hormones potentiate nucleotides as proinflammatory mediators and we hypothesize that they have bearing on the hyperfiltration seen in diabetes.

Adenosine Triphosphate↗
PubMed2001

Both platelet-derived growth factor receptor (PDGFR)-alpha and PDGFR-beta promote murine fibroblast cell migration.

Cell motility plays a critical role for many physiological and pathological processes including wound healing, fibrosis, angiogenesis, and tumor metastasis. Platelet-derived growth factor (PDGF) is among the most potent stimuli for mesenchymal cell migration. The PDGF B-chain homodimer PDGF BB activates both alpha- and beta-receptor subunits (alpha-PDGFR and beta-PDGFR), and promotes cell migration in many cell types including fibroblasts and smooth muscle cells. PDGF-A chain homodimer PDGF AA activates alpha-PDGFR only, and its role for cell migration is still debatable. PDGF BB, but not PDGF AA, induces smooth muscle cell migration. Interestingly, alpha-PDGFR was shown to antagonize beta-PDGFR-induced smooth muscle cell migration. In the present study, we investigated the role of alpha-PDGFR and beta-PDGFR in PDGF-mediated cell migration of murine fibroblasts (NIH 3T3). Unlike smooth muscle cells, both PDGF AA and PDGF BB promoted NIH 3T3 cell migration. The effect of PDGF BB activation of beta-PDGFR alone for cell migration was examined using previously established NIH 3T3 clones in which alpha-PDGFR signaling is inhibited by a dominant-negative alpha-PDGFR, or an antisense construct of alpha-PDGFR. PDGF BB activation of beta-PDGFR alone was sufficient to induce cell migration, but the efficiency was significantly lower compared to PDGF activation of both receptors. These results showed that both alpha- and beta-PDGFRs promote fibroblast cell migration and their effects are additive. Taken together, we propose that cell-type specific alpha-PDGFR signaling is critical for regulation of mesenchymal cell migration in response to PDGF isoform, whereas beta-PDGFR mainly promotes cell migration.

3T3 Cells↗
PubMed2002

Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells.

Tube formation of endothelial cells is an important step of angiogenesis. However, little is known about the molecular mechanisms underlying growth factor-mediated tube formation by endothelial cells. FGF-2 stimulates tube formation by a murine brain capillary endothelial cell line, IBE cells, when cultured on collagen gels (differentiation-associated culture condition), whereas cells proliferate and migrate without forming tube on fibronectin-coated surface (proliferation/migration-associated condition). To elucidate FGF-2-mediated signal transduction pathways leading to tube formation by endothelial cells, we focused on the contribution of Src family kinases. Src family kinase inhibitor PP2 attenuated FGF-2-induced tube formation. Stable expression of kinase-inactive c-Src in IBE cells demonstrated no dominant negative effect on FGF-2-induced tube formation. In vitro kinase assay revealed that c-Fyn was activated by FGF-2 only in cells cultured on collagen gels. Three independent cell lines, expressing kinase-inactive c-Fyn, all exhibited attenuation of FGF-2-mediated tube formation. However, FGF-2-mediated proliferation or migration was not clearly perturbed in these cells. These results show the first time that c-Fyn plays a pivotal role in tube formation by endothelial cells.

Animals↗
PubMed1995

Platelet-derived growth factor.

Platelet-derived growth factor (PDGF) is a potent activator for cells of mesenchymal origin. Two different PDGF chains termed A and B encoded by different genes have been identified leading to three different PDGF isoforms, the AA and BB homodimers and the AB heterodimer. All three forms have been observed in vivo and possess biological activity in vitro with the AA homodimer being the poorest cellular mitogen. The availability of highly purified recombinant PDGF isoforms was the initial basis for comparative studies in order to specify the different spectra of activity of the various PDGF species. This review is particularly focused on AB heterodimer as from the standpoint of heterologous gene expression, this species is the one with the highest demands concerning expression and purification protocols. This explains the fact that, in comparison to PDGF-BB, only very limited data on the in vivo application of PDGF-AB are available so far.

Animals↗
PubMed1995

Regulation of fibronectin expression by PDGF-BB and IGF-I in cultured rat thoracic aortic adventitial fibroblasts.

Regulation of fibronectin (FN) by Platelet-derived Growth Factor-BB (PDGF-BB) and Insulin-like Growth Factor-I (IGF-I) in cultured rat thoracic aortic adventitial fibroblasts were examined. PDGF-BB enhances FN mRNA levels in a time and concentration-dependent fashion. The effect of IGF-I on PDGF-BB-induced FN levels was also examined. There was a larger increase in FN mRNA levels (4-fold) in the cells treated with both IGF-I and PDGF-BB than with either IGF-I (2-fold) or PDGF-BB (2-fold) alone. The effects of PDGF-BB and IGF-I on FN levels were examined. There was a larger increase in FN levels (135%) in the cells treated with both PDGF-BB and IGF-I than with either PDGF-BB (43%) or IGF-I (45%) alone. Regulation of adventitial fibroblast FN may lead to blood vessel diseases and/or angiogenesis.

Animals↗
PubMed1999

PDGF-BB and IGF-I use different signaling pathways to induce NaK-ATPase subunits in cultured rat thoracic aortic smooth muscle cells.

(Na(+)+K(+))-adenosine triphosphatase (NaK-ATPase), an ubiquitous membrane transport protein consisting of alpha and beta subunits, regulates Na(+)/K(+)fluxes and maintains many vital physiological functions, including cell growth. Results have indicated that platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I) both enhance NaK-ATPase subunits. Genistein, an inhibitor of tyrosine phosphorylation, inhibits serum- and PDGF-BB-induced NaK-ATPase alpha(1)subunit protein levels without inhibiting IGF-I-induced NaK-ATPase alpha(1)subunit protein levels. These results indicate that PDGF-BB and IGF-I utilize separate signaling pathways to induce the synthesis of NaK-ATPase alpha(1)subunits. In addition, genistein failed to inhibit PDGF-BB-stimulated NaK-ATPase beta(1)subunit levels, suggesting that two separate pathways are involved to induce the synthesis of the NaK-ATPase alpha(1)and beta(1)subunits, respectively.

Animals↗
PubMed2001

PDGF-BB and IGF-I use different signaling pathways to induce fibronectin synthesis in cultured rat thoracic aortic smooth muscle cells.

Fibronectin, an extracellular matrix protein, acts as an early signal in initiating cell proliferation. Results have indicated that platelet-derived growth factor BB (PDGF-BB) and insulin-like growth factor-I (IGF-I) both enhance fibronectin gene expression. Genistein inhibits PDGF-BB-induced fibronectin levels without inhibiting IGF-I-induced fibronectin levels. It indicates that PDGF-BB and IGF-I utilize separate signaling pathways to induce the synthesis of fibronectin.

Animals↗
PubMed1997

Activation of NK1.1+ T cells in vitro and their possible role in age-associated changes in inducible IL-4 production.

Interleukin (IL)-12 or IL-4 produced early in an immune response directs the differentiation of naive antigen-activated CD4+ T cells down a Th1 or Th2 pathway. The NK1.1+ subset of T cells promptly produces IL-4 following activation in vivo. We demonstrate here that NK1.1+ T cells can be directly induced to produce IL-4 in vitro when activated under serum-free culture conditions. Platelet-derived growth factor in cell culture medium was inhibitory to the production of IL-4 by NK1.1+ T cells in vitro. Lymphocytes obtained from secondary lymphoid organs of aged mice produced greater quantities of IL-4 following stimulation than lymphocytes from mature adult animals. Aged mice expressed elevated percentages of NK1.1+ T cells in their secondary lymphoid organs and peripheral blood. While this cell type was responsible for the total early IL-4 produced by lymphocytes from mature adult mice, both NK1.1+ and memory phenotype (CD44high, CD45RBlow, NK1.1-) T cells from aged donors produced IL-4 following polyclonal T cell activation.

Actins↗
PubMed2000

Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair.

Fetal wound healing is characterized by minimal inflammation and scarless repair. IL-6 stimulates inflammation in postnatal wound healing. We hypothesized that fetal skin has a diminished IL-6 response and that exogenous IL-6 will result in scar formation. Human adult or fetal skin was placed subcutaneously in SCID mice and incisionally wounded. Wounds were excised after 4, 12, 24 or 72 h for IL-6 mRNA quantification by RT-PCR. In other grafts, 5 microgram of IL-6 was injected at wounding and then harvested at 7 days for analysis of scar formation. IL-6 production was examined in primary cultures of human fetal or adult dermal fibroblasts incubated for 8 h with 0, 0.1, 1 or 10 ng/ml of PDGF-BB. IL-6 mRNA was detected 4 h after wounding in fetal and adult wounds, but by 12 h there was no IL-6 mRNA in the fetal wounds. Adult wounds had IL-6 mRNA persisting to 72 h. IL-6 administration to fetal wounds resulted in scar formation. Fetal fibroblasts produced less IL-6 protein and mRNA at all points examined (P<0.01 vs adult). Diminished production of inflammatory cytokines such as IL-6 may be responsible for the lack of inflammation seen during fetal wound healing. Diminished inflammation may provide a permissive environment for scarless wound healing.

Adult↗
PubMed1994

Human cytotrophoblast invasion is up-regulated by epidermal growth factor: evidence that paracrine factors modify this process.

Formation of the human placenta requires a subset of cytotrophoblast stem cells to acquire an invasive phenotype. We examined the effect on cytotrophoblast invasiveness of growth factors that control the differentiation of other cells. Exogenous TGF-beta 1, PDGF-AA, PDGF-BB, and TNF-alpha affected neither cell morphology nor the rate of cytotrophoblast invasion in vitro. In contrast, addition of EGF to first trimester cytotrophoblast cultures produced dramatic changes in morphology and a severalfold increase in invasive capacity. The effects of EGF on later gestation cytotrophoblasts, whose invasive capacity is diminished, were much less pronounced. Next we investigated whether cytotrophoblasts themselves produce ligands that interact with the EGF receptor. A radioimmunoassay and a radioreceptor assay failed to detect EGF receptor ligands in cytotrophoblast-conditioned medium. Likewise, by RT-PCR cytotrophoblasts expressed neither EGF nor TGF-alpha mRNA. In contrast, EGF receptor mRNA was expressed and its protein levels remained constant during the experiment. Immunolocalization using F(ab') fragments of an anti-human EGF antibody failed to detect this growth factor in the chorionic villus. We conclude that maternal ligands that interact with the EGF receptor could play an important role by up-regulating trophoblast invasion, particularly during the early stages of pregnancy.

Becaplermin↗