scholarly journals Differential modulation of degradative and repair responses of interleukin-1-treated chondrocytes by platelet-derived growth factor

1993 ◽  
Vol 292 (1) ◽  
pp. 129-136 ◽  
Author(s):  
A K Harvey ◽  
S T Stack ◽  
S Chandrasekhar
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Proteinase Activity ◽  
Proteoglycan Synthesis ◽  
Mrna Levels ◽  
The Matrix

Interleukin 1 (IL-1) plays a dual role in cartilage matrix degeneration by promoting extracellular proteinase action such as the matrix metalloproteinases (increased degradation) and by suppressing the synthesis of extracellular matrix molecules (inhibition of repair). Platelet-derived growth factor (PDGF) is a wound-healing hormone which is released along with IL-1 during the inflammatory response. Since previous studies have shown that PDGF enhances IL-1 alpha effects on metalloproteinase activity, in this report, we have examined whether PDGF modifies IL-1 beta effects on cartilage proteoglycan synthesis. Initially, we confirmed that rabbit articular chondrocytes treated with IL-1 beta + PDGF induced higher proteinase activity, in comparison with IL-1-treated cells. We further observed that the increased proteinase activity correlated with an increase in the synthesis of collagenase/stromelysin proteins and a corresponding increase in the steady-state mRNA levels for both the enzymes. Studies on IL-1 receptor expression suggested that PDGF caused an increase in IL-1 receptor expression which, by augmenting the IL-1 response, may have led to the increase in proteinase induction. Analysis of proteoglycan synthesis confirmed that IL-1 reduced the incorporation of sulphated proteoglycan, aggrecan, into the extracellular matrix of chondrocytes, whereas PDGF stimulated it. However, cells treated with IL-1 + PDGF synthesized normal levels of aggrecan. This is in contrast with cells treated with IL-1 + fibroblast growth factor, in which case only proteinase activity was potentiated. The results allow us to conclude that (a) the two effector functions that play a role in matrix remodelling, namely matrix lysis (proteinase induction) and matrix repair (proteoglycan synthesis), occur via distinct pathways and (b) PDGF may play a crucial role in cartilage repair by initially causing matrix degradation followed by promoting new matrix synthesis.

scholarly journals Repression of platelet-derived growth factor beta-receptor expression by mitogenic growth factors and transforming oncogenes in murine 3T3 fibroblasts.

1995 ◽  
Vol 15 (3) ◽  
pp. 1244-1253 ◽  
Author(s):  
C Vaziri ◽  
D V Faller
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Growth Arrest ◽  
Serum Deprivation ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Mrna Levels ◽  
Beta Receptor ◽  
3T3 Fibroblasts

Platelet-derived growth factor BB (PDGF-BB) is an important extracellular factor for regulating the G0-S phase transition of murine BALB/c-3T3 fibroblasts. We have investigated the expression of the PDGF beta receptor (PDGF beta R) in these cells. We show that the state of growth arrest in G0, resulting from serum deprivation, is associated with increased expression of the PDGF beta R. When the growth-arrested fibroblasts are stimulated to reenter the cell cycle by the mitogenic action of serum or certain specific combinations of growth factors, PDGF beta R mRNA levels and cell surface PDGF-BB-binding sites are markedly downregualted. Oncogene-transformed 3T3 cell lines, which fail to undergo growth arrest following prolonged serum deprivation, express constitutively low levels of the PDGF beta R mRNA and possess greatly reduced numbers of cell surface PDGF receptors, as determined by PDGF-BB binding and Western blotting (immunoblotting). Nuclear runoff assays indicate the mechanism of repression of PDGF beta R expression to be, at least in large part, transcriptional. These data indicate that expression of the PDGF beta R is regulated in a growth state-dependent manner in fibroblasts and suggest that this may provide a means by which cells can modulate their responsiveness to the actions of PDGF.

scholarly journals Interleukin-1 β regulation of fibroblast proteoglycan synthesis involves a decrease in versican steady-state mRNA levels

1993 ◽  
Vol 294 (2) ◽  
pp. 613-620 ◽  
Author(s):  
E E Qwarnström ◽  
H T Järveläinen ◽  
M G Kinsella ◽  
C O Ostberg ◽  
L J Sandell ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Steady State ◽  
Chondroitin Sulphate ◽  
Interleukin 1 ◽  
Mrna Level ◽  
Three Dimensional ◽  
Proteoglycan Synthesis ◽  
Mrna Levels ◽  
Pronounced Decrease

This study investigates the effects of interleukin (IL)-1 beta on proteoglycan metabolism by fibroblasts surrounded by endogenous extracellular matrix. In both three-dimensional matrix cultures and long-term monolayer cultures IL-1 beta caused a significant decrease in synthesis and deposition of sulphated proteoglycans, but had no effect on release of deposited material. The decrease in synthesis became successively more pronounced, and corresponded to 40-60% of the control after 72 h incubation. The reduction was almost totally accounted for by an effect on the chondroitin ABC-lyase-sensitive proteoglycans. Gel electrophoresis showed a significant decrease in a high-molecular-mass chondroitin ABC-lyase-sensitive proteoglycan after incubation with IL-1 beta. Northern-blot analyses of total RNA revealed a pronounced decrease in the steady-state mRNA levels of versican, the large chondroitin sulphate, with levels corresponding to 10-30% of controls. In comparison, the steady-state mRNA level for decorin, the major sulphated proteoglycan synthesized by the cells, was only slightly affected. The prominent decrease in synthesis of sulphated proteoglycans induced in long-term fibroblast cultures, including the pronounced decrease in versican steady-state mRNA levels, is likely to have a significant effect on the structure of the extracellular matrix. Induction of this type of change may constitute a significant mechanism whereby IL-1 beta can affect the properties of connective tissue during inflammation and wound healing.

scholarly journals Platelet-derived growth factor potentiates cellular responses of articular chondrocytes to interleukin-1

1991 ◽  
Vol 34 (6) ◽  
pp. 697-706 ◽  
Author(s):  
Robert J. Smith ◽  
James M. Justen ◽  
Laurel M. Sam ◽  
Norman A. Rohloff ◽  
Patricia L. Ruppel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Cellular Responses ◽  
Platelet Derived Growth Factor

scholarly journals Down-regulation of cellular platelet-derived growth factor receptors induced by an activated neu receptor tyrosine kinase.

1991 ◽  
Vol 2 (8) ◽  
pp. 651-661 ◽  
Author(s):  
L Lehtola ◽  
M Nistér ◽  
E Hölttä ◽  
B Westermark ◽  
K Alitalo
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Target Cells ◽  
Mrna Levels ◽  
Pdgf Receptor ◽  
Down Regulation ◽  
Beta Receptors ◽  
Neu Oncogene

The functional integration of growth factor signaling occurs at several levels in target cells. One of the most proximal mechanisms is receptor transmodulation, by which one activated receptor can regulate the expression of other receptors in the same cells. Well-established transregulatory loops involve platelet-derived growth factor (PDGF) down-regulation of epidermal growth factor (EGF) receptors and beta-type transforming growth factors modulation of PDGF receptors. We have studied the relationship between neu tyrosine kinase activation and the expression of the PDGF receptors in transfected NIH/3T3 cells. Expression of the neu oncogene, but not of the neu proto-oncogene, was associated with a decrease of PDGF alpha- and beta-receptors on the cell surface, as measured by [125-I]PDGF-AA and -BB binding. These results were corroborated by metabolic labeling and immunoprecipitation of the PDGF beta-receptors. PDGF alpha- and beta-receptor mRNAs were strongly decreased in the neu oncogene-transformed cells in comparison with control cells expressing the neu proto-oncogene. Down-regulation of the PDGF receptors and their mRNAs was also observed after EGF treatment of cells expressing a chimeric EGF receptor/neu receptor, where the neu tyrosine kinase is activated by EGF binding. These results show that the neu tyrosine kinase can down-modulate PDGF receptor expression, and the effect is mediated via decreased PDGF receptor mRNA levels.

scholarly journals Modulatory role of platelet-derived growth factor on cytokine-induced nerve growth factor synthesis in rat glomerular mesangial cells

1995 ◽  
Vol 312 (3) ◽  
pp. 707-711 ◽  
Author(s):  
K M A Plüss ◽  
J Pfeilschifter ◽  
H Mühl ◽  
A Huwiler ◽  
C Boeckh ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Platelet Derived Growth Factor ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Glomerular Mesangial Cells ◽  
Peripheral Tissues ◽  
Nerve Growth

Recent evidence indicates that cytokines are potent inducers of nerve growth factor (NGF) expression in peripheral tissues and in brain. Cultured rat glomerular mesangial cells respond to interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) by increased NGF synthesis. We found that co-stimulation of rat glomerular mesangial cells with platelet-derived growth factor (PGDF-BB) and IL-1 beta/TNF-alpha significantly augments the IL-1 beta/TNF-alpha-induced NGF mRNA levels and NGF synthesis. In contrast, preincubation with PDGF-BB drastically reduces NGF gene expression and NGF protein synthesis in response to IL-1 beta/TNF-alpha stimulation. Thus our results indicate that PDGF-BB is a potent modulator of cytokine-induced NGF expression; its precise action is critically depending on the time at which the PDGF receptor is activated.

scholarly journals Myc Is an Essential Negative Regulator of Platelet-Derived Growth Factor Beta Receptor Expression

2000 ◽  
Vol 20 (18) ◽  
pp. 6768-6778 ◽  
Author(s):  
Sara K. Oster ◽  
Wilson W. Marhin ◽  
Charlotte Asker ◽  
Linda M. Facchini ◽  
Patrick A. Dion ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Cell Types ◽  
Receptor Expression ◽  
Negative Regulator ◽  
Platelet Derived Growth Factor ◽  
Mrna Levels ◽  
Proliferating Cells ◽  
Receptor Complexes ◽  
Β Receptor

ABSTRACT Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF β receptor (PDGF-βR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-βR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-βr mRNA expression. Our studies show that pdgf-βr mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-βr mRNA and protein. Suppression of pdgf-βr mRNA in response to Myc is specific, since expression of the related receptorpdgf-αr is not affected. We further show that Myc suppresses pdgf-βr mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-βr mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-βr mRNA levels plays an important role in the regulation of basalpdgf-βr expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-βR.

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