Presentation: Enhanced Activation of Mitogen-Activated Protein Kinases in Rheumatoid Arthritis Synovial Tissue is Selectively Associated with Angiogenesis and Erosive Joint Disease (2007)

138 Enhanced Activation of Mitogen-Activated Protein Kinases in Rheumatoid Arthritis Synovial Tissue is Selectively Associated with Angiogenesis and Erosive Joint Disease

Background: p38, p42/44 (ERK) and Jun kinase (JNK) mitogen-activated protein kinases (MAPKs) are activated in rheumatoid arthritis (RA) synovial tissue and are thought to play a central role in coordinating cellular proliferation, activation, and survival in RA. However, conflicting studies have reported differential requirements for p38 and JNK in animal models of arthritis, and the relative contributions of activity of each MAPK to cellular and clinical parameters of RA have not been studied.
Objective: To assess the relative activation of MAPKs in RA and psoriatic arthritis (PsA) patient synovial tissue and their relationships with cellular and clinical parameters of disease activity.
Materials and Methods: Arthroscopic synovial biopsies were obtained from 20 RA and 20 PsA patients with active disease. Expression and or phosphorylation of p38, ERK, and JNK, as well as MMP-1, MMP-3, TNF, and Tie2 were determined using specific antibodies for immunohistochemical analysis. Stained synovial tissue sections were evaluated by computer-assisted image analysis. MAPK activation was compared between patients with erosive and non-erosive disease, and correlations assessed between patient clinical parameters and the degree of MAPK activation.
Results: Activation of p38 was significantly higher in RA synovial tissue than in PsA synovial tissue (p= 0.0024). ERK activation was significantly elevated in the synovial sublining RA patients compared to PsA (p=0.0108). No differences in JNK activation were noted between RA and PsA. Within the RA patient cohort, we observed a positive correlation between ERK (R=0.457; p=0.0021), and JNK (R=0.485; p=0.0027) activation and expression of angiogenic Tie2, but not TNF or MMPs. No correlations between MAPK activation and cytokine or MMP expression were observed in PsA. ERK (p= 0.015) and p38 activation (p=0.0195) in the intimal lining layer, and JNK activation (p=0.001) in the synovial sublining, was elevated in patients with erosive RA as compared to patients with non-erosive RA.
Conclusion: Our studies provide the first evidence that different MAPKs contribute to specific cellular and clinical parameters of disease activity in RA. In particular, targeting MAPKs may be useful in preventing joint erosion in RA, while ERK and/or JNK inhibitors suppress angiogenesis.
Disclosure statements:
Work supported by a grant from Array BioPharma
D. Trollinger, Array BioPharma employment
Work supported by the Dutch Artritis Foundation

 D. de Launay, None; T. Smeets, None; M. Vinkenoog, None; D. Groot, None; D. Trollinger, None; P.P. Tak, None; K.A. Reedquist, None.