Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1β and association with β1-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 β1-integrin. Superficial osteoarthritic chondrocytes exhibited VEGFR-3 expression in the cytoplasm and on the cell membrane. Using western blotting we could demonstrate that interleukin-1β (IL-1β) 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 β1-integrin and VEGFR-3 in IL-1β-stimulated chondrocytes indicating that activated VEGFR-3 may interact with β1-integrin and associated subcellular pathways in osteoarthritic chondrocytes. Taken together with results of previous studies showing that β1-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 β1-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.