ARTHRITIS & RHEUMATISM Vol. 44, No. 12, December 2001, pp 2888–2898 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc. Adenovirus-Based Overexpression of Tissue Inhibitor of Metalloproteinases 1 Reduces Tissue Damage in the Joints of Tumor Necrosis Factor  Transgenic Mice Georg Schett, 1 Silvia Hayer, 1 Makiyeh Tohidast-Akrad, 2 Beatrice Jahn Schmid, 1 Susanne Lang, 1 Birgit Tu ¨rk, 1 Franz Kainberger, 1 Sylva Haralambous, 3 George Kollias, 3 Andrew C. Newby, 4 Qingbo Xu, 5 Gu ¨nter Steiner, 6 and Josef Smolen 6 Objective. Rheumatoid arthritis is a prototype of a destructive inflammatory disease. Inflammation trig- gered by the overexpression of tumor necrosis factor  (TNF) is a driving force of this disorder and mediates tissue destruction. Since matrix metalloproteinases (MMPs) are among the molecules activated by TNF, we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), in TNF transgenic mice could inhibit the development of destructive arthritis. Methods. Systemic treatment was carried out by replication-defective adenoviral vectors for TIMP-1, -galactosidase, or phosphate buffered saline (PBS), which were applied once at the onset of arthritis. Clinical, serologic, radiologic, and histologic outcomes were assessed 18 days after the treatment. Results. The AdTIMP-1 group showed signifi- cantly reduced paw swelling and increased grip strength compared with the 2 control groups, whereas total body weight, TNF, and interleukin-6 levels were similar in all 3 groups. Radiographic assessment revealed a sig- nificant reduction of joint destruction in the AdTIMP-1 group; this was confirmed by histologic analyses show- ing reduced formation of pannus and erosions in the AdTIMP-1 group compared with the AdLacZ and PBS control groups. The formation of arthritis-specific au- toantibodies to heterogeneous nuclear RNP A2 was not observed in the AdTIMP-1 group but was present in the 2 control groups. Conclusion. These results indicate a central role of MMPs in TNF-mediated tissue damage in vivo and a promising therapeutic role for TIMP-1. Rheumatoid arthritis (RA) is a systemic inflam- matory disease characterized by severe structural alter- ations of the joint architecture, including the destruction of cartilage and bone. In recent years, tumor necrosis factor  (TNF) has been recognized as a central pathogenic molecule in RA (1), and experimental ani- mals overexpressing TNF develop synovitis with ac- companying destruction of cartilage and bone (2–4). TNF is also overexpressed in RA synovial membranes (5), and growing evidence from animal models and human RA suggests that TNF, besides its role as a proinflammatory mediator, has an important, at least indirect, effect on joint destruction. Blockage of TNF in TNF transgenic mice (6) and in humans with RA (7–9) has been shown to significantly retard joint dam- age, suggesting that the effector pathways of joint dam- age are TNF driven. One central effector pathway may represent the induction of matrix metalloproteinases (MMPs) (10–13), although others, such as interleukin-1 (IL-1)–associated mechanisms (14) and the induction of osteoclastogenesis (15–18), seem to play additional im- portant roles. Supported by the Interdisciplinary Cooperative Project of the Austrian Ministry of Sciences and the City of Vienna. 1 Georg Schett, MD, Silvia Hayer, Beatrice Jahn Schmid, MD, Susanne Lang, MD, Birgit Tu ¨rk, Franz Kainberger, MD: University of Vienna, Vienna, Austria; 2 Makiyeh Tohidast-Akrad, PhD: Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Aus- tria; 3 Sylva Haralambous, PhD, George Kollias, MD: Hellenic Pasteur Institute, Athens, Greece; 4 Andrew C. Newby, MD: Bristol Heart Institute, Bristol, UK; 5 Qingbo Xu, MD, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria, and St. George’s Hospital Medical School, London, UK; 6 Gu ¨nter Steiner, PhD, Josef Smolen, MD: University of Vienna and Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Aus- tria. Address correspondence and reprint requests to Georg Schett, MD, Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Wa ¨hringer Gu ¨rtel 18-20, A-1180 Vienna, Austria. E-mail: georg.schett@akh-wien.ac.at. Submitted for publication April 5, 2001; accepted in revised form July 26, 2001. 2888