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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047825-03
Application #
6752854
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
2002-06-15
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$250,040
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Stanford, Stephanie M; Aleman Muench, German R; Bartok, Beatrix et al. (2016) TGF? responsive tyrosine phosphatase promotes rheumatoid synovial fibroblast invasiveness. Ann Rheum Dis 75:295-302
Schepetkin, Igor A; Kirpotina, Liliya N; Hammaker, Deepa et al. (2015) Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor. J Pharmacol Exp Ther 353:505-16
Doody, Karen M; Stanford, Stephanie M; Sacchetti, Cristiano et al. (2015) Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci Transl Med 7:288ra76
Boyle, David L; Hammaker, Deepa; Edgar, Meghan et al. (2014) Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PLoS One 9:e84818
Stanford, Stephanie M; Maestre, Michael F; Campbell, Amanda M et al. (2013) Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival. Arthritis Rheum 65:1171-80
Bottini, Nunzio; Firestein, Gary S (2013) Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 9:24-33
Lee, Sang-il; Boyle, David L; Berdeja, Andres et al. (2012) Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthritis Res Ther 14:R38
Guma, Monica; Firestein, Gary S (2012) c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. Open Rheumatol J 6:220-31
Guma, Monica; Hammaker, Deepa; Topolewski, Katharyn et al. (2012) Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis Rheum 64:2887-95

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