Shiozawa Shunichi, Tsumiyama Ken
Division of Rheumatology, Department of Medicine, Kobe University Graduate School of Medicine, and The Center for Rheumatic Diseases, Kobe University Hospital, Chuoku, Kobe, Japan.
Cell Cycle. 2009 May 15;8(10):1539-43. doi: 10.4161/cc.8.10.8411. Epub 2009 May 13.
c-Fos/AP-1 controls the expression of inflammatory cytokines and matrix-degrading matrix metalloproteinases (MMPs) important in arthritis via promoter AP-1 binding motif. Among inflammatory cytokines, IL-1beta is the most important inducer of a variety of MMPs, and mainly responsible for cartilage breakdown and osteoclastogenesis. IL-1beta and c-Fos/AP-1 influence each other's gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, where TNFalpha can act synergistically with them. While how to stop the degradation of bone and cartilage, i.e., to control MMP, has long been the central issue in the research of rheumatoid arthritis (RA), selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction. Thus, the blockade of IL-1beta and/or c-Fos/AP-1 can be promising as an effective therapy for rheumatoid joint destruction in addition to the currently available TNFalpha blocking agents that act mainly on arthritis.
c-Fos/AP-1 通过启动子 AP-1 结合基序控制对关节炎至关重要的炎性细胞因子和基质降解性基质金属蛋白酶（MMPs）的表达。在炎性细胞因子中，IL-1β 是多种 MMPs 的最重要诱导剂，主要负责软骨破坏和破骨细胞生成。IL-1β 与 c-Fos/AP-1 相互影响彼此的基因表达和活性，导致一种协调的相互作用，这对关节炎关节破坏至关重要，其中 TNFα 可与它们协同作用。虽然如何阻止骨和软骨的降解，即控制 MMP，长期以来一直是类风湿性关节炎（RA）研究的核心问题，但选择性抑制 c-Fos/AP-1 确实可解决关节炎关节破坏问题。因此，除了目前主要作用于关节炎的 TNFα 阻断剂外，阻断 IL-1β 和/或 c-Fos/AP-1 有望成为治疗类风湿性关节破坏的有效疗法。
