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

Citation
G. Schett et al., Adenovirus-based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor alpha transgenic mice, ARTH RHEUM, 44(12), 2001, pp. 2888-2898
Citations number
56
Categorie Soggetti
Rheumatology,"da verificare
Journal title
ARTHRITIS AND RHEUMATISM
ISSN journal
00043591 → ACNP
Volume
44
Issue
12
Year of publication
2001
Pages
2888 - 2898
Database
ISI
SICI code
0004-3591(200112)44:12<2888:AOOTIO>2.0.ZU;2-F
Abstract
Objective. Rheumatoid arthritis is a prototype of a destructive inflammator y disease. Inflammation triggered by the overexpression of tumor necrosis f actor alpha (TNF alpha) is a driving force of this disorder and mediates ti ssue destruction. Since matrix metalloproteinases (MMPs) are among the mole cules activated by TNF alpha, we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), in TN F alpha transgenic mice could inhibit the development of destructive arthri tis. Methods. Systemic treatment was carried out by replication-defective adenov iral vectors for TIMP-1, beta -galactosidase, or phosphate buffered saline (PBS), which were applied once at the onset of arthritis. Clinical, serolog ic, radiologic, and histologic outcomes were assessed 18 days after the tre atment. Results. The AdTIMP-1 group showed significantly reduced paw swelling and i ncreased grip strength compared with the 2 control groups, whereas total bo dy weight, TNF alpha, and interleukin-6 levels were similar in all 3 groups . Radiographic assessment revealed a significant reduction of joint destruc tion in the AdTIMP-1 group; this was confirmed by histologic analyses showi ng 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 AdT IMP-1 group but was present in the 2 control groups. Conclusion. These results indicate a central role of MMPs in TNF alpha -med iated tissue damage in vivo and a promising therapeutic role for TIMP-1.