Adenovirus‐based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor α transgenic mice

Objective

Rheumatoid arthritis is a prototype of a destructive inflammatory disease. Inflammation triggered by the overexpression of tumor necrosis factor α (TNFα) is a driving force of this disorder and mediates tissue destruction. Since matrix metalloproteinases (MMPs) are among the molecules activated by TNFα, we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP‐1), in TNFα transgenic mice could inhibit the development of destructive arthritis.

Methods

Systemic treatment was carried out by replication‐defective adenoviral vectors for TIMP‐1, β‐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 significantly reduced paw swelling and increased grip strength compared with the 2 control groups, whereas total body weight, TNFα, and interleukin‐6 levels were similar in all 3 groups. Radiographic assessment revealed a significant reduction of joint destruction in the AdTIMP‐1 group; this was confirmed by histologic analyses showing reduced formation of pannus and erosions in the AdTIMP‐1 group compared with the AdLacZ and PBS control groups. The formation of arthritis‐specific autoantibodies 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 TNFα‐mediated tissue damage in vivo and a promising therapeutic role for TIMP‐1.