Role of integrin alpha11beta1 in joint destruction in inflammatory arthritis.

The project deals with the role of integrin alpha11 in rheumatoid arthritis (RA) using a genetic mosue model, the hTNFtg mice. Starting point for project was based on the finding that that beta1 integrins are involved in the attachment of synovial fibroblasts (effector cells in RA) to components of the extracellular matrix and, upon attachment, regulate migratory and invasive processes. The group of Adelheid Korb-Pap could already show that integrin alpha11- integrin is expressed at increased levels both in human RA synovial fibroblasts and in the hTNFtg mice vs. controls. Isolated hTNFtg synovial fibroblasts showed - in line with the human data – an increase of alpha11- integrin expression levels. - Analyses in various functional assays showed a reduced proliferation rate and invasiveness of Itga11-/- fibroblasts (isolated from Itga11-/- mice provided by Donald Gullberg) - In vivo evaluations of offspring from Itga11-/- and hTNFtg mice revealed a milder arthritis score and less cartilage and bone destructions in Itga11-/-hTNFtg compared to hTNFtg mice. Remaining questions to be addressed in the project period : - Determine how the activation of alpha11- integrin is involved in the transformation of synovial fibroblasts and subsequently in cell adhesion and invasion resulting in cartilage destruction. - Determine if alpha11 integrin contributes to fibroblast heterogeneity in the synovial tissue. - Determine if the specific inhibition of alpha11- integrin activation may serve as a therapeutic target