Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1? and association with ?1-integrins

Abstract

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.

Onset and Progression of Human Osteoarthritis—Can Growth Factors, Inflammatory Cytokines, or Differential miRNA Expression Concomitantly Induce Proliferation, ECM Degradation, and Inflammation in Articular Cartilage?

“…Expression of the VEGF receptors VEGFR-1, also known as Fms related tyrosine kinase 1 (FLT-1) and VEGFR-2, also known as kinase insert domain receptor (KDR) is either restricted to OA AC compared to normal AC [115], whereas other studies reported that VEGFR-1 [116] or VEGFR-2 [119] were not detectable at all in human adult AC. Moreover, in human OA AC VEGFR-3, also known as Fms-like tyrosine kinase 4 (FLT4), is expressed in the SZ cells located in cytoplasm and on cell membrane [120]. In primary OA AC monolayer cultures catabolic MMP-1 and MMP-3 mRNA expression, but not MMP-2 , MMP-9 or MMP-13 expression, can be induced by rVEGF165, whereas cultured normal AC cells exhibit no catabolic gene expression upon rVEGF165 treatment at all [115].…”

VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification

“…It is required for the development of blood as well as lymphatic vessels and is thought to have a general function in blood vascularization during early development (Lohela et al, 2003); later, its role becomes restricted mostly to the development of the lymphatic vascular system (Dayoub et al, 2003). Furthermore, expression of VEGFR-3 has been reported to be higher in human osteoarthritic chondrocytes than in persons without arthritis (Shakibaei et al, 2003).…”

VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome

“…[12][13][14] The ␣ v ␤ 3 integrin associates with KDR in endothelial cells, 13 whereas the ␤ 1 subunit forms a functional complex with VEGFR-3 in chondrocytes. 15 Moreover, soluble FLT-1 secreted by endothelial cells binds to ␣ 5 ␤ 1 integrin. 16 Finally, a membrane complex containing PKC, ␤ 1 integrin, and FLT-1 has been shown to assemble in multiple myeloma cells.…”