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

Am J Pathol. 2001 Nov;159(5):1711-21. doi: 10.1016/s0002-9440(10)63018-0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Antigens / immunology
  • Arthritis / complications
  • Arthritis / drug therapy*
  • Arthritis / immunology
  • Arthritis / pathology*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / physiopathology
  • Binding Sites
  • Binding, Competitive
  • Biomarkers
  • Cartilage, Articular / drug effects*
  • Cartilage, Articular / pathology*
  • Cell Adhesion Molecules / metabolism
  • Cell Adhesion Molecules / therapeutic use*
  • Edema / etiology
  • Edema / pathology
  • Hyaluronic Acid / metabolism
  • Knee Joint / drug effects
  • Knee Joint / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Preventive Medicine / methods
  • Proteoglycans / immunology
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / therapeutic use
  • Time Factors

Substances

  • Anti-Inflammatory Agents
  • Antigens
  • Biomarkers
  • Cell Adhesion Molecules
  • Proteoglycans
  • Recombinant Proteins
  • Tnfaip6 protein, mouse
  • Hyaluronic Acid