Rheumatoid arthritis (RA) is a chronic inflammatory arthritis marked by synovial hyperplasia with local invasion of bone and cartilage. Accumulating evidence suggests that RA fibroblast-like synoviocytes (FLS), which form the leading destructive front of rheumatoid synovium, possess unique characteristics and contribute to cartilage degradation. Recently, we have demonstrated that RA FLS activate the Jun N- terminal kinase (JNK) pathway efficiently and that this kinase is phosphorylated in RA synovium. To explore the potential relationship between JNK activation and joint damage in RA, we will evaluate the signal transduction and transcription factor pathways involved in matrix metalloproteinase gene regulation, cartilage invasion, and joint destruction. In particular, we will determine the contribution of the mitogen-activated protein kinase (MAPK) family. Our preliminary experiments suggest that JNK is a key regulatory element in the machinery involved in joint destruction. In addition, IL-1-induced JNK phosphorylation is increased in RA and this pathway appears to regulate collagenase gene expression. We propose to test the hypothesis that JNK is a target for development of chondroprotective agents in arthritis using two unique tools: 1) SP600125, the first small molecule selective JNK inhibitor; and 2) JNK knockout mice. First, we will determine the role of JNK in synoviocyte metalloproteinase production, cytokine expression, and invasion into cartilage. Second, we will determine the upstream signal transduction pathways that regulate JNK in RA FLS and determine the mechanism of increased JNK activation in RA compared with osteoarthritis. Finally, we will determine the role of JNK in animal models of arthritis. These data will support our hypothesis that JNK plays a pivotal role in the FLS biology and is a potential target for chondroprotective therapy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Mancini, Marie
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Stanford, Stephanie M; Svensson, Mattias N D; Sacchetti, Cristiano et al. (2016) Receptor Protein Tyrosine Phosphatase ?-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice. Arthritis Rheumatol 68:359-69
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