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. Previous studies demonstrated that cytokines activate Jun N-terminal kinase (JNK) in FLS, that this kinase is phosphorylated in RA synovium, and that JNK regulates joint damage in animal models of arthritis. Two upstream kinases, MKK4 and MKK7, can independently activate JNK and initiate protease and cytokine gene expression. In contrast to this shared function in other cell types, our preliminary data suggests that MKK7 is the primary pathway for cytokine- and Toll-like receptor (TLR) 2 and 4--mediated JNK activation in synoviocytes and that MKK4 only participates in limited responses to certain cellular stresses (e.g., TLR3 activation and anisomysin). Over-activation of JNK in RA synovium and synoviocytes might be due, in part, to deficient expression Gadd45ss, which can function as an endogenous MKK7-JNK inhibitor. We hypothesize that MKK7 is a potential therapeutic target that modulates pro-inflammatory gene expression in synoviocytes, thereby influencing a subset of JNK functions involved in the pathogenesis of RA, while leaving other functions regulated by MKK4 in intact. To test this hypothesis, we will determine the role of MKK4, MKK7, and Gadd45ss in murine models of inflammatory arthritis. Second, we will explore the mechanisms and functional sequelae of MKK7 activation in cultured synoviocytes. Third, we will examine how Gadd45ss and upstream kinases like TAK 1 regulate MKK4 and MKK7 activation in FLS. These data will test the hypothesis that the JNK pathway plays a pivotal role in the synoviocyte biology and is a potential target for chondroprotective therapy.

Public Health Relevance

. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis play a major role in joint destruction by virtue of their ability to produce proteases and cytokines. This process is mediated, in part, by signal transduction pathways like c-Jun N-terminal kinase (JNK). This project will explore how JNK in RA is regulated by upstream kinases and determine the potential for inhibiting one of these signaling molecules as a therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047825-10
Application #
8312636
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2001-07-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$290,737
Indirect Cost
$102,558
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
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
Luo, Yubin; Boyle, David L; Hammaker, Deepa et al. (2011) Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45?-deficient mice. Arthritis Rheum 63:2949-55
Guma, Monica; Ronacher, Lisa M; Firestein, Gary S et al. (2011) JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis. Arthritis Rheum 63:1603-12
Kolker, S J; Walder, R Y; Usachev, Y et al. (2010) Acid-sensing ion channel 3 expressed in type B synoviocytes and chondrocytes modulates hyaluronan expression and release. Ann Rheum Dis 69:903-9
Fukushima, Akihisa; Boyle, David L; Corr, Maripat et al. (2010) Kinetic analysis of synovial signalling and gene expression in animal models of arthritis. Ann Rheum Dis 69:918-23
Bartok, Beatrix; Firestein, Gary S (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233-55
Blewis, Megan E; Lao, Brian J; Jadin, Kyle D et al. (2010) Semi-permeable membrane retention of synovial fluid lubricants hyaluronan and proteoglycan 4 for a biomimetic bioreactor. Biotechnol Bioeng 106:149-60
Scatizzi, John C; Hutcheson, Jack; Pope, Richard M et al. (2010) Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis. Arthritis Rheum 62:441-51

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