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

类风湿性关节炎(RA)以关节软骨和骨的破坏为特征，破骨细胞是RA骨吸收的主要细胞类型。因此，破骨细胞是治疗类风湿关节炎的真正靶点。在本研究中，我们发现抗炎细胞因子IL-4和IL-10通过抑制小鼠骨髓细胞中的c-Fos而抑制破骨细胞的分化。此外，我们还发现腺相关病毒载体IL-4有效地感染破骨细胞的前体单核细胞，并抑制肿瘤坏死因子α介导的人外周单核细胞的破骨细胞生成，提示腺相关病毒IL-4基因治疗可能是一种有前途的治疗类风湿关节炎的方法。此外，我们还证实了一类新型抗炎化合物--过氧化物酶体增殖物激活受体γ(PPARγ)的激动剂能抑制肿瘤坏死因子α介导的人单核细胞破骨细胞的生成，这种抑制作用可能部分是通过抑制单核细胞趋化因子-1来实现的。综上所述，我们提出了两种治疗策略，AAV-IL-4基因治疗和PPARγ激动剂，用于类风湿关节破坏。我们希望这一项目能够为抗风湿药物的开发做出贡献。

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.