Mechanical forces trigger invasive behavior in synovial fibroblasts through N-cadherin/ADAM15 -dependent modulation...

Joint damage caused by immune-mediated inflammation in rheumatoid arthritis (RA) preferentially affects site-specific mechano-sensitive areas. The perception of physical forces in the synovial tissue by the residing fibroblasts initiates signalling responses with impact on cellular functions. Here, we describe a mechanotransduction pathway in rheumatoid arthritis synovial fibroblasts (RASF), which is critically dependent on the disintegrin metalloproteinase ADAM15 and N-cadherin (NCAD). Both molecules co-localize in NCAD-based adherens junctions and trigger mechanosignaling events involving the activation of p21-activated kinase 2 (PAK2). The mechanically induced phosphorylation of PAK2 subsequently leads to its co-recruitment together with the adaptor molecule Nck to the NCAD/ADAM15 complex at the cell membrane. These signal transduction events initiate strain-induced downregulation of lncRNA H19 and miR-130a-3p. They finally result in an upregulation of cadherin-11 (CDH11), thereby enhancing cell invasive properties - a feature characteristic of aggressive RASFs. Accordingly, we propose a new mechano-induced pathway that causes an altered composition of cadherin expression in the adherens junctions of synovial fibroblasts and likely contributes to the site-specific variability of the aggressive RASF-phenotype in RA-pathogenesis.