Volume 3 Supplement 1

Innovative Rheumatology: Gene and Cell Therapies of Arthritis and Related Autoimmune Disorders. Second International Meeting

Open Access

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

  • G Schett1, 2, 3, 4,
  • S Hayer1, 2, 3, 4,
  • M Tohidast-Akrad1, 2, 3, 4,
  • B Jahn-Schmid1, 2, 3, 4,
  • S Lang1, 2, 3, 4,
  • F Kainberger1, 2, 3, 4,
  • G Kollias1, 2, 3, 4,
  • AC Newby1, 2, 3, 4,
  • Q Xu1, 2, 3, 4,
  • G Steiner1, 2, 3, 4 and
  • JS Smolen1, 2, 3, 4
Arthritis Research & Therapy20013(Suppl 1):P30


Received: 6 April 2001

Published: 25 April 2001

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.

Authors’ Affiliations

Division of Rheumatology, Department of Internal Medicine III, University of Vienna
Department of Molecular Genetics, Hellenic Pasteur Institute
Bristol Heart Institute
Institute for Biomedical Aging Research, Austrian Academy of Sciences


© BioMed Central Ltd 2001