Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen-induced arthritis

Objective. The imbalance between matrix metalloproteinases (MMPs) 1, 3, and 9 and their specific inhibitor, tissue inhibitor of metalloproteinases I ( TIMP-1), is a critical step in cartilage injury and angiogenesis in arthrit is. To explore the therapeutic potential of TIMP-1 gene transfer in erosive arthritis, the effects of an adenoviral vector (Ad-TIMP-1) were assessed i n DBA/1 mice with collagen-induced arthritis (CIA). Methods. DBA/1 mice with CIA received an intravenous injection of replicati on-deficient adenovirus containing the human TIMP-1 gene or a control LacZ gene on day 28 postimmunization. The efficiency of gene transfer was determ ined by serum TIMP-1 detection, measurements of paw swelling, as well as ra diologic and histologic examination of the paws. Results. A single administration of Ad-TIMP-1 resulted in detectable serum levels of the exogenous protein for at least 13 days. The incidence and ons et of arthritis were not statistically modified after human TIMP-1 gene tra nsfer in DBA/1 mice compared with control mice. However, the severity of in flammation was statistically significantly increased in Ad-TIMP-1-treated m ice and a similar trend was observed in the histologic and radiologic score s. With regard to the mechanisms of the worsened effect in the Ad-TIMP-1-tr eated mice, we observed 1) higher serum levels of anti-type II collagen IgG 2a, 2) a significant increase in endogenous soluble tumor necrosis factor r eceptor I (TNFRI) in sera, and 3) increased labeling of mouse tumor necrosi s factor a and TNFRI within arthritic joints. Conclusion. These findings show that overexpression of TIMP-1 does not prev ent osteochondral injury in a mouse model of arthritis. Since MMPs have ove rlapping properties in terms of their roles in extracellular matrix degrada tion, angiogenesis, and shedding of cell surface adhesion molecules, cytoki nes, and cytokine receptors, the paradoxical results obtained suggest that TIMP-1 is probably not the main inhibitor to target.