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-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-alpha-trypsin inhibitor (IalphaI), increasing the protease inhibitory effect of IalphaI >100-fold. The TSG-6/IalphaI 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 microg) 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.
Bárdos
T
T
Department of Orthopedic Surgery, Section of Biochemistry and Molecular Biology, Rush University, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Kamath
R V
RV
Mikecz
K
K
Glant
T T
TT
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology; D001168:Arthritis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D001665:Binding Sites; D001667:Binding, Competitive; D015415:Biomarkers; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000627:therapeutic use*; D004487:Edema / Q000209:etiology / Q000473:pathology; D006820:Hyaluronic Acid / Q000378:metabolism; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011315:Preventive Medicine / Q000379:methods; D011509:Proteoglycans / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D000941:Antigens; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D011509:Proteoglycans; D011994:Recombinant Proteins; C513057:Tnfaip6 protein, mouse; D006820:Hyaluronic Acid