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 alpha levels and serum interleukin-1alpha levels compared with animals with arthritis. The mutation of cysteine at position 1 of TIMP-4 failed to block the development of AIA.


CONCLUSIONS
Our data indicate that TIMP-4 is a potent antiinflammatory 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.
Celiker
Mahmut Y
MY
Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA. celiker@lij.edu
Ramamurthy
Nungavaram
N
Xu
Jin-Wen
JW
Wang
Mingsheng
M
Jiang
Yangfu
Y
Greenwald
Robert
R
Shi
Y Eric
YE
D000818:Animals; D000893:Anti-Inflammatory Agents; D001169:Arthritis, Experimental / Q000517:prevention & control*; D001769:Blood / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007273:Injections, Intramuscular; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood; D007596:Joints / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000097792:Tissue Inhibitor of Metalloproteinase-4
D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000097792:Tissue Inhibitor of Metalloproteinase-4