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.
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