Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by increased production of cytokines, proliferation of fibroblast-like synoviocytes (FLS) and joint destruction. It is well known that the involved joints in RA are hypoxic. Hypoxia may play a role in the pathogenesis of RA. We thought that hypoxia might alter the production of cytokines by FLS and these changes could affect the biologic behaviors of FLS. Based on that, we investigated whether hypoxia affects the production of cytokines in FLS and the effect of these

changes on matrix metalloproteinases (MMPs) expression.

Methods: Fibroblast-like synoviocytes from human rheumatoid synovial tissue obtained duringjoint replacement surgery were cultured in vitro. Hypoxic culture was performed by incubating cells in BBL^Ⱂ Gaspak pouch^TM anaerobic system. After incubation under hypoxic condition for 24 hr, the concentrations of various cytokines in culture supernatants were determined by ELISA. To determine the effect of highly expressed cytokines on MMP expression, we performed ELISA of MMP-1, MMP-2 and MMP-3 in cultured FLS, after stimulation with respective cytokines.

Results: In hypoxic state, IL-6, IL-8 and vascular endothelial growth factor (VEGF) concentrations were significantly increased compared to those in normoxic condition. However, there were little differences in IL-1, IL-2, IL-4, TNF-α and TGF-β. Stimulation of FLS with IL-6 and IL-8 showed the increased concentrations of MMP-1, MMP-2 and MMP-3.

Conclusion: Hypoxic environment of rheumatoid synovium might affect FLS to produce proinflammatory and proangiogenic cytokine such as IL-6 and IL-8. These cytokines again could stimulate MMPs production in FLS leading to joint destruction.

Keywords: Rheumatoid arthritis, Fibroblast-like synoviocytes, Hypoxia, IL-6, IL-8, Metalloproteinase