Phosphorylation of extracellular signal regulated kinases 1 and 2 is specifically associated with angiogenic Tie 2 expression in the synovium of patients with active rheumatoid arthritis but not psoriatic arthritis

Introduction: Animal studies suggest important roles for the mitogen-activated protein kinases (MAPKs) p38, extracellular signal regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) in the perpetuation of inflammation and disease progression in rheumatoid arthritis (RA). The objective of this study was to determine the expression and activation of MAPKs, and their potential relationship with clinical and cellular parameters of disease, in patients with clinically active RA and psoriatic arthritis (PsA). Methods: Expression and phosphorylation of p38, ERK, and JNK was examined in arthroscopic synovial biopsies from 20 RA and 19 PsA patients by immunohistochemical analysis, using quantitative computer-assisted image analysis. Phosphorylated (p)-MAPK levels were related to patient clinical parameters and synovial expression of tumor necrosis factor α (TNFα), matrix metalloproteinase (MMP)-1, MMP-3, and the angiogenic receptor Tie2. Localization of p-MAPKs and Tie2 in distinct cell populations within synovial tissue was determined by immunofluorescent double staining. Results: No differences in the number of cells expressing p-p38, p-ERK, or p-JNK were observed between RA and PsA synovial tissue. However, the percentage of cells expressing JNK that had detectable p-JNK was elevated in PsA synovial tissue (p< 0.05). The relative phosphorylation of p38 (p < 0.05) and ERK (p< 0.05), but not JNK, compared to total expression of each MAPK, was significantly higher in RA synovial tissue than in PsA. MAPK phosphorylation status was not associated with clinical parameters of disease activity in RA or PsA, or with expression of MMP-1 or MMP-3. In RA, p-ERK was associated with increased Tie2 expression (R = 0.583, p < 0.01), while in PsA p-JNK was associated with expression of TNFα (R = 0.713, p < 0.01). In RA synovial tissue, Tie2 and p-ERK prominently colocalized to synovial macrophages. Conclusion: In patients with clinically active arthritis, relative participation of p38 and ERK signaling in synovial tissue distinguishes RA from PsA. However, there is no clear association of MAPK activation with clinical parameters of disease activity in these forms of arthritis. ERK phosphorylation is intimately associated with Tie2 expression in RA, primarily in synovial macrophages, while in PsA, JNK phosphorylation is associated with TNF production. Our results suggest that activation of specific MAPKs is differentially linked to angiogenesis and inflammation in RA and PsA. 97 Ras Family GTPase Signaling Contributions to Inflammation and Joint Destruction in Rheumatoid Arthritis