Synoviocyte endothelial cell cross talk in rheumatoid arthritis

ABSTRACT The management of rheumatoid arthritis (RA) has been transformed by immune targeted disease-modifying anti- rheumatic agents such as tumor necrosis factor alpha inhibitors. However, an unmet need persists for therapies that would be more tailored against local and disease-specific mechanisms and thus be less immunosuppressive. The application of genomic approaches to the study of cells and tissues from patient synovium has recently allowed scientists to focus on the complex relationship between different cell types and between cells and matrix in RA synovium. This brough a renewed attention to the role of stromal joint cells such as fibroblast like synoviocytes (FLS) and blood vessel endothelial cells (EC). It has been recently observed that cells similar to FLS are found in the circulation of patients with RA suggesting that FLS can egress the synovium through blood vessels. However, transvascular FLS migration has not been reported in RA and its mechanisms remain unknown. We have collected initial evidence of FLS transmigration through EC layers in the synovium of RA patients and a mouse model of RA and have data suggesting that vascular FLS transmigration promotes vascular permeability in vivo. We also have developed an in vitro system to study RA FLS-EC transmigration process and collected evidence that transmigration of FLS alters the phenotype of EC. Finally, we have identified a gene that selectively controls the transmigration of RA FLS through EC layers. The aims of this grant are to validate a pathway that we believe connects FLS transmigration with EC-mediated inflammation using RA synovial specimens, in vitro and in vivo models (Aim 1), and assess whether the FLS gene that we have discovered influences FLS transmigration and arthritis severity (Aim 2).