Abstract Gribus

Platelet-derived growth factor receptor activation promotes the pro-destructive invadosome-forming phenotype of rheumatoid arthritis synoviocytes

Erosive joint damage leads to functional disability in rheumatoid arthritis (RA) but strategies for direct interference with the erosion process are lacking. Receptor tyrosine kinases (RTKs) have been implicated in the pathogenesis of various diseases including RA and cancer and are considered as potential therapeutic targets. Recent results indicate that synoviocyte invasion and cartilage degradation involve formation of matrix-degrading invadosomal structures but the mechanisms that trigger their formation are not clearly understood. Phospho-specific RTK antibody arrays were used to screen RA synovial cells for common RTKs. The involvement of PDGFR in invadosome formation was determined using invadopodia assays, PDGFR kinase inhibitor and neutralizing antibodies. Our study  shows that, among the common RTKs, PDGFR-αβ is specifically phosphorylated in synovial cells of RA patients, in contrast to cells of osteoarthritic or non-arthritic (NA) patients. Addition of PDGF increased functional invadosome formation in NA synovial cells up to the levels observed in RA cells. In contrast, neutralization of endogenous PDGFs or targeted inhibition of PDGFR kinase activity completely inhibited invadosome formation and ECM degradation in RA synoviocytes. Our data also indicate association between PDGF and TGFβ for invadosome formation that involves autocrine production of PDGF ligands induced by TGFβ.  We further showed that activation of the PI3K/AKT pathway were required for PDGFR-induced invadosome formation in RA synoviocytes. Taken together, these data suggest that PDGFR is a critical RTK required for the pro-destructive phenotype of RA synovial cells and thus a potential target for novel therapies sibling cartilage degradation and joint damage.                                    

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