When compared to single gene transfer, combination of IL-1Ra and IL-10 overexpression showed the strongest additive effect resulting in both decrease of perichondrocytic cartilage degradation and reduction of invasion of fibroblasts into the cartilage. IL-1Ra and IL-10 double gene transfer resulted also in distinct alterations of gene expression of molecules involved in cell activation and metabolism. In contrast, double gene transfer with TNFαRp55 did not improve the beneficial effects of IL-10 or those of IL-1Ra. Moreover, triple gene transfer using these three inhibitory molecules partly antagonized the benficial effects observed in double gene transfer both in the SCID mouse as well as on the molecular level.