possible therapeutic application of gene therapy of anti-inflammatory cytokines to rheumatoid joint destruction

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Rheumatoid Arthritis (RA) is characterized by destruction of joint cartilage and bone, and osteoclasts are the principal cell type responsible for bone resorption in RA. Therefore, osteoclasts are real targets for the treatment of RA. In this study, we found that IL-4 and IL-10, anti-inflammatory cytokines, inhibited osteoclast differentiation via suppression of c-Fos in murine bone marrow cells. In addition, we showed that adeno-associated virus vector of IL-4 (AAV-IL-4) efficiently infected monocytes, precursor of osteoclasts, and that AAV-IL-4 inhibited TNFα-mediated osteoclastogenesis from human peripheral monocytes, suggesting that AAV-IL-4 gene therapy may be a promising therapeutic applicant for RA. Furthermore, we demonstrated that agonists of peroxisome proliferator-activated receptor γ (PPARγ), a new class of anti-inflammatory compounds, inhibited TNFα-mediated osteoclasts generation in human monocytes, and the inhibitory effect may be mediated in part by suppression of monocyte chemoattractant-1 (MCP-1). In summary, we proposed two types of therapeutic strategy, AAV-IL-4 gene therapy and PPARγ agonist, for rheumatoid joint destruction. We hope this project may contribute to the development of anti-rheumatic drugs.