Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1 beta and association with beta 1-integrins.
Recent studies have demonstrated enhanced expression of vascular endothelial growth factor and vascular endothelial growth factor receptor (VEGFR)-1 and -2 in chondrocytes of rheumatoid and osteoarthritic cartilage. Since expression of VEGFR-3 ( Flt-4) in chondrocytes has not yet been investigated, we studied the distribution of VEGFR-3 in osteoarthritic cartilage samples by immunohistochemistry and immunoelectron microscopy. Furthermore, we looked for functional colocalization of VEGFR-3 with the signal transduction receptor beta(1)-integrin. Superficial osteoarthritic chondrocytes exhibited VEGFR-3 expression in the cytoplasm and on the cell membrane. Using western blotting we could demonstrate that interleukin-1 beta (IL-1 beta) stimulates the expression of VEGFR-3 in chondrocytes in vitro in a dose-dependent manner. By coimmunoprecipitation assay we found a functional complex between the beta(1)-integrin and VEGFR-3 in IL-1 beta-stimulated chondrocytes indicating that activated VEGFR-3 may interact with beta(1)-integrin and associated subcellular pathways in osteoarthritic chondrocytes. Taken together with results of previous studies showing that beta(1)-integrins were also associated with other surface receptors and proteins in chondrocytes that cause cartilage destruction in arthritis (for example, urokinase-type plasminogen activator receptor and matrix metalloproteinases), we can hypothesize that signal transduction by these receptor complexes via beta(1)-integrins may play a crucial role in pathogenesis of osteoarticular disorders. Further work needs to be done to elucidate downstream signaling events activated by these receptors.
Shakibaei
M
M
Institute of Anatomy, Freie Universität Berlin, Königin-Luise-Strasse 15, 14195 Berlin, Germany.
Schulze-Tanzil
G
G
Mobasheri
A
A
Beichler
T
T
Dressler
J
J
Schwab
W
W
D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D016253:Microscopy, Immunoelectron; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
D019012:Integrin beta1; D007375:Interleukin-1; D040321:Vascular Endothelial Growth Factor Receptor-3