Adenoviral-based overexpression of TIMP-1 reduces tissue damage in the joints of TNF-alpha transgenic mice

Chronic inflammation frequently entails the remodelling and/or destruction of the involved tissues. This is illustrated by human diseases and animal models characterized by TNF-α overexpression, such as rheumatoid arthritis and TNF-α transgenic mice, in which severe joint destruction is spontaneously observed in conjunction with chronic synovial inflammation. The detailed molecular mechanisms of TNF-α-mediated tissue damage are, however, unknown. Since matrix metalloproteinases are among the molecules activated by TNF-α we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases (TIMP)-1, in TNF-α-transgenic mice, could inhibit the development of destructive arthritis. Such adenoviral-based overexpression of TIMP-1 strongly inhibited spreading of inflammation and bone resorption, whereas treatment with the LacZ-control vector had no effect. This inhibition of tissue remodelling and damage by TIMP-1 was also associated with a significant reduction in clinical signs of arthritis and prevention of development of autoimmune phenomena. We conclude that matrix metalloproteinases are major effector molecules of TNF-α-triggered tissue damage and that the highly effective inhibition by TIMP-1 should be considered in the treatment of human disease.