Drs. Reedquist and Tak contributed equally to this work.
Local Synovial Engagement of Angiogenic TIE-2 Is Associated With the Development of Persistent Erosive Rheumatoid Arthritis in Patients With Early Arthritis
Article first published online: 27 NOV 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 12, pages 3073–3083, December 2013
How to Cite
van de Sande, M. G. H., de Launay, D., de Hair, M. J. H., García, S., van de Sande, G. P. M., Wijbrandts, C. A., Gerlag, D. M., Reedquist, K. A. and Tak, P. P. (2013), Local Synovial Engagement of Angiogenic TIE-2 Is Associated With the Development of Persistent Erosive Rheumatoid Arthritis in Patients With Early Arthritis. Arthritis & Rheumatism, 65: 3073–3083. doi: 10.1002/art.38128
- Issue published online: 27 NOV 2013
- Article first published online: 27 NOV 2013
- Accepted manuscript online: 27 AUG 2013 03:30PM EST
- Manuscript Accepted: 6 AUG 2013
- Manuscript Received: APR 2013
- European Union Sixth Framework Programme (project AutoCure)
- Dutch Arthritis Association. Grant Numbers: NR 04-1-301, NR 09-1-405
- Xunta de Galicia (Angeles Alvariño Postdoctoral Fellowship)
To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis.
Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease-modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang-1), Ang-2, TIE-2, and activated p–TIE-2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang-1, and Ang-2 were measured by enzyme-linked immunosorbent assay. Secreted products of macrophages stimulated with Ang-1 and Ang-2 were measured using a multiplex system.
Expression of Ang-1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE-2 and p–TIE-2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang-1 significantly enhanced the tumor necrosis factor–dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE-2 activation predicted the development of erosive disease (R2 = 0.35, P < 0.05).
Local engagement of synovial TIE-2 is observed during the earliest phases of RA, suggesting that TIE-2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE-2 signaling may be useful in improving outcome in arthritis.