FRI0074 Adenoviral-based overexpression of timp-1 reduces tissue damage in the joints of tnf-a-transgenic mice. (1st June 2001)

• Record Type: Journal Article
• Authors: Schett, G; Hayer, S; Tohidast-Akrad, M; Xu, Q; Kollias, G; Steiner, G; Smolen, J
• Is Part Of: Annals of the rheumatic diseases. Volume 60(2001)Supplement 1
• Page Start: A476
• Page End: A476
• Publication Date: 2001-06-01
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2001.1203
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Rheumatoid arthritis is a prototype of a destructive inflammatory disease. Inflammation triggered by the overexpression of TNF-a is a driving force of this disorder and mediates tissue destruction. The particular impact of TNF-a-induced molecules, such as matrix metalloproteinases, in tissue destruction is however unknown. Objectives: 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. Methods: 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 applied once at the onset of arthritis. Clinical, serological, radiological and histological outcomes were assessed 18 days after the treatment. Results: The AdvTIMP1 group showed a significantly reduced paw swelling and increased grip strength compared to the two control groups, whereas total body weight, TNF-a and IL-6 levels were similar in all three groups. Radiological assessment revealed a significant reduction of joint destruction in the AdvTIMP1 group; this was confirmed by histological analyses, showing reduced formation of pannus as well as erosions in the AdvTIMP1 group as compared to the AdvLacZ- and PBS- control groups. The formation of arthritis-specific autoantibodies to hnRNP-A2 was not observed in the AdvTIMP1 group but was present in the two control groups. Conclusion: These results indicates a central role of matrix metalloproteinases in TNF-a-mediated tissue damage in vivo and a promising therapeutic role of TIMP-1.