The role of Yes-associated protein kinase YAP1 in canonical and non-canonical Hippo pathway in the disintegrin metalloproteinase ADAM15-mediated anoikis resistance of synovial fibroblasts in rheumatoid arthritis

• Applicant: Professor Dr. Harald Burkhardt
• Subject Area: Rheumatology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438801991

Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatic joint disease. Based on genetic predispositions aberrantly dysregulated immunological effector cascades lead to chronic inflammatory reactions, resulting in the proteolytic destruction of cartilage and bone, thus compromising the integrity of articular joints. A major cell population critical for these destructive processes are the synovial fibroblasts, which are activated in the inflamed synovial membrane and secrete matrix degrading enzymes. A hallmark of rheumatoid arthritis synovial fibroblasts (RASFs) is their pathophysiological increased apoptosis resistance. Also RASFs, freely swimming in inflamed synovial fluid, are vital after their loss of matrix contact, which usually induces apoptosis, thereby rendering them anoikis resistant. The underlying mechanism of their acquired anoikis resistance are poorly understood, albeit pathophysiological relevant due to their capability to expand and infiltrate into joint tissues within one affected joint, and moreover their potential to migrate into distant healthy cartilage via the circulatory system, as has been demonstrated by animal studies.In our previous studies, a marked upregulated expression of the disintegrin metalloproteinase ADAM15 has been demonstrated in synovial membranes of RA patients. Moreover, this increased ADAM15 expression confers anti-apoptotic effects upon ligation of the death receptor Fas/CD95. The aim of the present study is to analyze, whether the transcriptional coactivator YAP1 confers cytoprotective properties in (non)-canonical Hippo pathway dependent on ADAM15 upon anoikis induction in RASFs. Therefore, ADAM15-dependent YAP1-mediated signalling pathways elicited by anoikis induction will be characterized in RASFs. Based on the outcome, the application of specific signal transduction inhibitors to selectively inhibit YAP1 signalling, thereby blocking the increased anoikis resistance of RASFs, will be evaluated. Additionally, YAP1 upstream adhesion molecules and receptors will be identified as well as YAP1 downstream gene targets.The aim of the study is the elucidation of ADAM15-dependent molecular interactions in YAP1 signaling in the anoikis resistance of RASFs and the identification of new targets for a pharmacological inhibition of these aggressively destructive synovial cell population in RA.

• DFG Programme: Research Grants