Function and Regulation of the Transmembrane Glycoprotein Podoplanin in Inflammatory Bone Destruction in Rheumatoid Arthritis

• Applicant: Dr. Corinna Wehmeyer
• Subject Area: Rheumatology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319464273

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterised by progressive loss of the joint structure. The membrane-bound glycoprotein podoplanin (PDPN) is upregulated in subtypes of RA-synovial fibroblasts (RA-FLS) by the inflammatory cytokines TNFalpha, IL-1 beta and TGF-beta and plays an important role in the communication between RA-FLS and platelet microparticles in the RA-synovium, promoting inflammatory processes. The only known receptor for PDPN is CLEC-2, a c-type lectin receptor, which is highly expressed by platelets, inflammatory dendritic cells and macrophages and is responsible for RA-FLS-platelet interaction. Based on my preliminary results about the expression of PDPN in osteocytes and CLEC-2 expression in osteoclasts of arthritic mice, I would like to address the question of how PDPN is involved in osteoblast/osteocyte-osteoclast communication and thus how it affects the pathogenesis of RA. In particular, I want to focus on the hypothesis that a direct cell-cell interaction between osteocytes or osteoblasts and osteoclasts by PDPN and CLEC-2 in arthritic joints is associated with enhanced bone resorption by osteoclasts leading to enhanced bone loss. To investigate the functional importance of PDPN during the development of a destructive arthritis, the K/BxN serum transfer-induced arthritis model will be performed in PDPN deficient mice. Additionally, in vitro investigations on the regulation of PDPN as well as functional studies using co-cultures of primary osteoclasts with osteoblasts and osteocytes will provide new insights into the mechanisms of bone destruction during RA and will help to develop new therapeutic approaches.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Christopher Buckley