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