Inhibition of forkhead box class O family member transcription factors in rheumatoid synovial tissue

• Published in: Arthritis and rheumatism 2007-07, Vol.56 (7), p.2180-2191
• Main Authors: Ludikhuize, J., de Launay, D., Groot, D., Smeets, T. J. M., Vinkenoog, M., Sanders, M. E., Tas, S. W., Tak, P. P., Reedquist, K. A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Biopsy; Blood Sedimentation; Diseases of the osteoarticular system; Female; Fibroblasts - physiology; Forkhead Box Protein O1; Forkhead Transcription Factors - antagonists & inhibitors; Goats; Humans; Immunohistochemistry; Inflammatory joint diseases; Macrophages - pathology; Male; Medical sciences; Middle Aged; Miscellaneous. Osteoarticular involvement in other diseases; Osteoarthritis; Osteoarthritis - blood; Osteoarthritis - genetics; Osteoarthritis - pathology; Phosphorylation; Rabbits; Synovial Membrane - pathology
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.22653

Objective Phosphatidylinositol 3‐kinase–dependent activation of protein kinase B (PKB) has been observed in rheumatoid arthritis (RA) synovial tissue, and mechanisms that interfere with this process are protective in animal models of arthritis. PKB can regulate cell survival and proliferation via phosphorylation‐dependent inactivation of forkhead box class O (FoxO) transcription factors. The present study was undertaken to examine whether FoxO transcription factors are differentially inactivated in RA synovial tissue, and whether this inactivation correlates with laboratory and clinical parameters of disease activity. Methods The expression and phosphorylation of FoxO family members were assessed in synovial biopsy tissue from 12 patients with RA and 9 patients with inflammatory osteoarthritis (OA), by immunohistochemistry and quantitative computer‐assisted image analysis. Immunoblotting was used to assess the interleukin‐1β (IL‐1β)– and tumor necrosis factor α (TNFα)–induced phosphorylation of FoxO1 and FoxO4 in cultured fibroblast‐like synoviocytes (FLS) and macrophages. Results FoxO1, FoxO3a, and FoxO4 were expressed and phosphorylated in synovial tissue from both RA patients and OA patients. In RA synovial tissue, phosphorylation of FoxO1 was observed in both FLS and macrophages, FoxO3a in T lymphocytes, and FoxO4 in macrophages alone. Following stimulation with IL‐1β and TNFα, FoxO1 and FoxO4 were phosphorylated in both RA and OA FLS and synovial macrophages, respectively. Inactivation of FoxO4 was significantly enhanced in the RA as compared with the OA synovial sublining. There was a strong negative correlation between inactivation of FoxO4 in RA synovial tissue and increased serum C‐reactive protein levels and a raised erythrocyte sedimentation rate in RA patients. Conclusion All 3 FoxO family members examined were phosphorylated in both RA and OA synovial tissue; in particular, inactivation of FoxO4 was significantly enhanced in macrophages from RA synovial tissue. Thus, cell‐specific inactivation of FoxO family members appears to differentially regulate cell survival and proliferation in the RA synovium.