Chondroitin sulfate prevents platelet derived growth factor-mediated phosphorylation of PDGF-Rbeta in normal human fibroblasts severely impairing mitogenic responses.
Platelet-derived growth factor (PDGF) is a major polypeptide mitogen for cells of mesenchymal origin such as fibroblasts. Chondroitin sulfate chains (CS), which are abundant in the extracellular matrix have been shown to physically interact with PDGF-BB modulating its biological function. The aim of the present study was to examine the involvement of CS on PDGF-BB induced proliferative responses and receptor activation in human lung fibroblasts. The addition of exogenous free CS chains caused a significant downregulation of the PDGF-BB mediated mitogenic and chemotactic responses. Similar results were obtained by the increase of endogenous CS biosynthesis after beta-D-xyloside treatment. Furthermore, removal of the membrane-bound CS chains by selective enzymatic treatment significantly increased the proliferative capacity of human fibroblasts. Analysis of PDGF-R phosphorylation in the presence of CS or beta-D-xyloside, revealed a reduction of PDGF-Rbeta phosphorylation in the tyrosine residue 1021. These results demonstrate, for the first time, that CS either soluble or surface bound downregulates the mitogenic responses of PDGF-BB in normal human lung fibroblasts through the reduction of PDGF-Rbeta phosphorylation.
Fthenou
E
E
Department of Histology, Medical School, University of Crete, 71003 Heraklion, Greece.
Zafiropoulos
A
A
Katonis
P
P
Tsatsakis
A
A
Karamanos
N K
NK
Tzanakakis
G N
GN
D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D002809:Chondroitin Sulfates / Q000494:pharmacology* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006027:Glycosides / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology* / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
D006027:Glycosides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C010807:xylosides; D000077214:Becaplermin; D002809:Chondroitin Sulfates; D020797:Receptor, Platelet-Derived Growth Factor beta