Gene therapy offers a radically different approach to the treatment of arthritis. We demonstrated that cDNA coding for human interleukin-1 receptor-antagonist protein (IL-1Ra) and cDNA coding for human interleukin-10 (IL-10) can be delivered, by ex vivo techniques, to the synovial lining of joints, intra-articular expression of gene significantly reduced cartilage matrix degradation and cartilage breakdown. To achieve this, lapine synoviocytes were first transduced in culture by retroviral infection. The genetically modified synoviocytes were then transplanted by intra-articular injection into the knee joints of OA rabbits, assay of joint lavages confirmed that the gene expression was not lost 14 days after transfer. Knees receiving the IL-1Ra gene had significantly reduced cartilage breakdown. Delivery of the IL-10 gene was less effective, having only a moderate effect on cartilage breakdown. When both genes were injected together, there was a greater inhibition of cartilage breakdown, suggesting that simultaneous gene delivery may be necessary to treat OA by targeting the activities of multiple inflammatory effectors.