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Volume 3 Supplement 2

21st European Workshop for Rheumatology Research

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


Rheumatoid arthritis is a prototype of a destructive inflammatory process. Inflammation triggered by the overexpression of TNF-a is recognized as a driving force of the disease process and mediated tissue destruction. The particular impact of TNF-a-dependent pathways in tissue destruction is unknown.

Materials and methods

Herein, the effect of an overexpression of tissue inhibitor of metalloproteinases (TIMP)-1, a physiological antagonist of metalloproteinases, was studied in the arthritis model of TNF-a-transgenic mice. Systemic treatment was carried out by replication defective adenoviral vectors for TIMP-1 (AdvTIMP1, n =7) or b-galactosidase (AdvLacZ, n = 6) or phosphate buffered saline (PBS, n = 7), which were injected once intravenously at the onset of arthritis. Clinical, serological, radiological and histological outcomes were assessed 18 days after treatment.


The AdvTIMP1 group showed a significantly improved clinical outcome as measured by paw swelling and grip strength than the two control groups, whereas total body weight, TNF-a and IL-6 levels were similar in all groups. Tissue destruction as assessed by X-ray and histology of hind paws was significantly lower in the AdvTIMP1 group than in the AdvLacZ- and PBS- control groups. Finally, the formation of arthritis-specific autoantibodies to hnRNP-A2 was not observed in the AdvTIMP1 group but were present in the two control groups.


These results indicates a central role of metalloproteinases in TNF-a-mediated tissue damage in vivo and a promising therapeutic role of TIMP-1.

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Schett, G., Hayer, S., Xu, Q. et al. Adenoviral-based overexpression of TIMP-1 reduces tissue damage in the joints TNF-transgenic mice. Arthritis Res Ther 3 (Suppl 2), P088 (2001).

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