Production of cytokines, vascular endothelial growth factor, matrix metalloproteinases, and tissue inhibitor of metalloproteinases 1 by tenosynovium demonstrates its potential for tendon destruction in rheumatoid arthritis

Objective. To investigate the role of proinflammatory cytokines, vascular e ndothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and tiss ue inhibitor of metalloproteinases 1 (TIMP-1) in the destruction of tendons by tenosynovium in rheumatoid arthritis (RA). Methods. Synovial specimens were obtained from encapsulating tenosynovium ( n = 17), invasive tenosynovium (n = 13), and wrist joints (n = 17) in 18 RA patients undergoing wrist extensor tenosynovectomy. Synovial membrane cell s were dissociated from connective tissue by enzyme digestion and cultured in vitro for 48 hours, and harvested supernatants were assayed for the cyto kines tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6), VEG F, MMPs 1, 2, 3, and 13, and TIMP-1 by enzyme-linked immunosorbent assay. G elatin zymography was performed to demonstrate enzyme activity. Statistical analysis was performed using Student's paired 2-tailed t-tests for paramet ric data and the Wilcoxon signed rank test for nonparametric data. Results. MMP-1 and MMP-13 levels were similar to2.5-fold higher in invasive tenosynovium compared with encapsulating tenosynovium. Levels of MMP-2 wer e similar to1.5-fold higher in invasive tenosynovium compared with both enc apsulating tenosynovium and wrist joint synovium. MMP-13 (P = 0.009) and IL -6 (P = 0.03) levels were significantly lower in encapsulating tenosynovium compared with wrist joint synovium. Levels of VEGF, TIMP-1, TNF alpha, and MMP-3 were similar in all synovial sample groups. Zymography demonstrated enzyme activity in all synovium samples from all 9 patients assessed. Conclusion. Tenosynovium. produces proinflammatory cytokines and proteolyti c enzymes that are important in the tissue degradation seen in RA. Increase d production of the enzymes MMP-1, MMP-2, and MMP-13 by invasive tenosynovi um suggests a possible explanation for the worse prognosis and increased ru pture rate associated with invasive tenosynovitis in RA. Production of VEGF by tenosynovium. suggests that angiogenesis may have a role in tenosynovia l proliferation and invasion of tendons.