Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis

Tumor necrosis factor-alpha (TNF-alpha)-stimulated gene-6 (TSG-6) is up-reg ulated by various cytokines and growth factors. TSG-6 binds to hyaluronan i n inflamed synovial tissue and forms a complex with a serine protease inter -alpha -trypsin inhibitor (I alphaI), increasing the protease inhibitory ef fect of I alphaI > 100-fold. The TSG-6/I alphaI complex then blocks serine proteases, including the plasminogen-plasmin activation, probably the most important component in the activation processes of matrix metalloproteinase s. To gain insight into the mechanisms of TSG-6 action in arthritis, we hav e used an autoimmune murine model (proteoglycan-induced arthritis) for syst emic, and a monoarticular form of arthritis (antigen-induced arthritis) for local treatment of arthritis with recombinant mouse TSG-6 (rmTSG-6). Intra venous injection of rmTSG-6 induced a dramatic reduction of edema in acutel y inflamed joints by immobilizing CD44-bound hyaluronan and, in long-term t reatment, protected cartilage from degradation and blocked subchondral and periosteal bone erosion in inflamed joints. The intra-articular injection o f a single dose (100 mug) of rmTSG-6 exhibited a strong chondroprotective e ffect for up to 5 to 7 days, preventing cartilage proteoglycan from metallo proteinase-induced degradation. In contrast, rmTSG-6 did not postpone the o nset, nor reduce the incidence of arthritis. We were unable to detect any s ignificant differences between control and rmTSG6-treated animals when vari ous serum markers (including pro- and anti-inflammatory cytokines, auto- an d heteroantibody productions) or antigen-specific T-cell responses were com pared, nor when the expressions of numerous cell surface receptors or adhes ion molecules were measured. TSG-6 seems to play a critical negative regula tory feed-back function in inflammation, especially in arthritic processes.