Inhibition of adjuvant-induced arthritis by systemic tissue inhibitor of metalloproteinases 4 gene delivery

Objective. An imbalance in the matrix metalloproteinase:tissue inhibitor of metalloproteinases (MMP: TIMP) ratio in favor of MMP appears to be an important determinant of tissue damage in arthritis. We undertook this study to explore whether reversal of this imbalance in favor of TIMP would alter this process and to examine the mechanism of this alteration. Methods. We administered human TIMP-4 by electroporation-mediated intramuscular injection of naked DNA using the rat adjuvant-induced arthritis (AIA) model. Results. Intramuscular naked TIMP-4 gene administration resulted in high circulating TIMP-4 levels and completely abolished arthritis development in the rat AIA model. This inhibition was associated with significantly decreased MMP activity in the joint tissue as well as with significantly decreased serum and tissue tumor necrosis factor a levels and serum interleukin-la levels compared with animals with arthritis. The mutation of cysteine at position 1 of TIMP-4 failed to block the development of AIA. Conclusion. Our data indicate that TIMP-4 is a potent anttinflammatory agent, and that its antiarthritis function may be mediated by MMPs. Arthritis-inhibiting effects of TIMP-4 may suggest a unique application of this gene therapy method for arthritis.