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(American Journal of Pathology. 2001;159:1711-1721.)
© 2001 American Society for Investigative Pathology

Regular Articles

Anti-Inflammatory and Chondroprotective Effect of TSG-6 (Tumor Necrosis Factor--Stimulated Gene-6) in Murine Models of Experimental Arthritis

Tamás Bárdos^*, Rajesh V. Kamath, Katalin Mikecz^* and Tibor T. Glant^*

From the Departments of Orthopedic Surgery^*
and Biochemistry,
Section of Biochemistry and Molecular Biology, Rush University, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois

Tumor necrosis factor- (TNF-)-stimulated gene-6 (TSG-6) is up-regulated by various cytokines and growth factors. TSG-6 binds to hyaluronan in inflamed synovial tissue and forms a complex with a serine protease inter--trypsin inhibitor (II), increasing the protease inhibitory effect of II >100-fold. The TSG-6/II complex then blocks serine proteases, including the plasminogen-plasmin activation, probably the most important component in the activation processes of matrix metalloproteinases. To gain insight into the mechanisms of TSG-6 action in arthritis, we have used an autoimmune murine model (proteoglycan-induced arthritis) for systemic, and a monoarticular form of arthritis (antigen-induced arthritis) for local treatment of arthritis with recombinant mouse TSG-6 (rmTSG-6). Intravenous injection of rmTSG-6 induced a dramatic reduction of edema in acutely inflamed joints by immobilizing CD44-bound hyaluronan and, in long-term treatment, protected cartilage from degradation and blocked subchondral and periosteal bone erosion in inflamed joints. The intra-articular injection of a single dose (100 µg) of rmTSG-6 exhibited a strong chondroprotective effect for up to 5 to 7 days, preventing cartilage proteoglycan from metalloproteinase-induced degradation. In contrast, rmTSG-6 did not postpone the onset, nor reduce the incidence of arthritis. We were unable to detect any significant differences between control and rmTSG-6-treated animals when various serum markers (including pro- and anti-inflammatory cytokines, auto- and heteroantibody productions) or antigen-specific T-cell responses were compared, nor when the expressions of numerous cell surface receptors or adhesion molecules were measured. TSG-6 seems to play a critical negative regulatory feed-back function in inflammation, especially in arthritic processes.

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