Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis

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PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding of how different types of synovial fibroblasts contribute to rheumatoid arthritis (RA) pathology, restricting the ability to block fibroblast-mediated joint inflammation and cartilage erosions. The long-term goal driving this proposal is to identify ways to specifically target fibroblast function in inflammatory arthritis. The objective of this proposal to investigate platelet-derived growth factor receptors (PDGFRs) as one of these targets. Although PDGFRs are potent stimulators of fibroblast proliferation and migration and are known to be upregulated in RA, PDGFR research in inflammatory arthritis has lagged behind other disease fields. The rationale for this study is that it will advance new therapeutic approaches in autoimmune inflammatory arthritis by both developing preclinical data to support an arthritis indication for newly developed anti-PDGFR therapeutics and by discovering novel fibroblast pathways for future clinical targeting. The central hypothesis shaping this proposal is that that PDGFRα and PDGFRβ independently contribute to the development of inflammatory arthritis and fibroblast-mediated joint pathology. This hypothesis is built on preliminary data showing different functional outcomes following PDGFRα or PDGFRβ activation in RA synovial fibroblasts and demonstrating that different fibroblast subpopulations can be isolated directly from the synovium based on PDGFRα and PDGFRβ expression. This hypothesis will be tested in three specific aims: (1) Determine how PDGFRα and PDGFRβ expression regulates inflammatory arthritis development; (2) Determine how PDGFRα and PDGFRβ activation is regulated in synovial fibroblasts; and (3) Test anti-PDGFR treatment combinations in a preclinical inflammatory arthritis model. Aim 1 uses inducible genetic deletion of PDGFRs to test their function in arthritis development in a mouse model and correlates this function with the transcriptional profiles of PDGFR-expressing fibroblast populations isolated directly from the synovium. Aim 2 isolates differential effects of PDGFRα and PDGFRβ activation in synovial fibroblasts by examining gene expression, membrane interactions, and ligand availability. Aim 3 uses the preclinical serum transfer mouse arthritis model to test how anti-PDGFR antibodies may augment arthritis treatment when combined with other types of therapies. This approach is innovative, in the applicant's opinion, because it reenergizes PDGFR research in RA by combining genetic tools developed for other diseases with new flow cytometric and bioinformatic methods to analyze fibroblast function both in vitro and directly ex vivo. The proposed research is significant because determining how PDGFRα and PDGFRβ expression and signaling regulates fibroblast and synovial biology is expected to assess how new PDGF-specific drugs can be used to treat RA and to increase our fundamental understanding of how different synovial fibroblast populations contribute to inflammatory arthritis pathogenesis.