Müller-Ladner U, Kriegsmann J, Gay R E, Gay S
Department of Medicine, University of Alabama at Birmingham 35294-0006, USA.
Rheum Dis Clin North Am. 1995 Aug;21(3):675-90.
The evolving knowledge of the actions and interactions of (proto)oncogenes in cancer has deeply influenced the understanding of other nonmalignant diseases. In RA, the longstanding pathohistologic evidence of transformed-appearing synovial cells at the site of bone and cartilage attachment and joint destruction can now be explained in terms of alterations of cell regulation, cell cycle, and apoptotically triggered cell death. The detection of upregulated oncogenes and their gene products at these sites supported the hypothesis of an aberrant synovial cell type invading the joint. Interestingly, there are hints that this transformation of synovial cells may require more than one activated oncogene. A model was introduced by Carson and Ribero in 1993. In this model, a primary stimulus affects the cell and leads to the enhanced transcription of an oncogene (i.e., c-myc). A second stimulus activates other oncogenes and determines if this cell (i.e., a synovial fibroblast) proliferates (marked by the presence of bcl-2 mRNA) or undergoes apoptosis (marked by fas mRNA and Fas expression at the cell surface). This co-upregulation might explain why some investigators could not detect a significant upregulation of oncogenes in cultured synovial fibroblasts devoid of their normal milieu. Based on the results of the specific activity of Fas and perforin and recent data from our laboratory, we have modified Carson's model to include these data. As there exists an established retroviral model in which the tax sequence of the HTLV retrovirus initiates central oncogene transcription similar to those activated in RA, the retroviral particles, which do not resemble any other known retrovirus but are detectable in the synovial fluid, might well be an important stimulus in the pathogenesis of RA. To simplify the puzzling events of oncogene interactions in RA, we have summarized the data and propose that an oncogene network acts as a pathogenic mechanism in the synoviocytes of the rheumatoid joint. Similar to the "cytokine network" regulating the T-cell-dependent pathway, the "oncogene network" is presumably the major T-cell-independent pathway in RA (Fig. 4).
对癌基因在癌症中的作用及相互作用的认识不断发展，这深刻影响了对其他非恶性疾病的理解。在类风湿关节炎（RA）中，长期以来在骨与软骨附着部位出现的形态改变的滑膜细胞以及关节破坏的病理组织学证据，现在可以从细胞调节、细胞周期及凋亡引发的细胞死亡的改变方面来解释。在这些部位检测到癌基因及其基因产物上调，支持了异常滑膜细胞类型侵入关节的假说。有趣的是，有迹象表明滑膜细胞的这种转变可能需要不止一种激活的癌基因。1993年卡森（Carson）和里韦罗（Ribero）提出了一个模型。在这个模型中，一个主要刺激作用于细胞，导致癌基因（即c - myc）转录增强。第二个刺激激活其他癌基因，并决定该细胞（即滑膜成纤维细胞）是增殖（以bcl - 2 mRNA的存在为标志）还是发生凋亡（以fas mRNA和细胞表面的Fas表达为标志）。这种共同上调可能解释了为什么一些研究人员在缺乏正常环境的培养滑膜成纤维细胞中未检测到癌基因的显著上调。基于Fas和穿孔素的比活性结果以及我们实验室的最新数据，我们对卡森的模型进行了修改以纳入这些数据。由于存在一个既定的逆转录病毒模型，其中人类嗜T淋巴细胞病毒（HTLV）逆转录病毒的tax序列启动类似于在RA中激活的核心癌基因转录，这种逆转录病毒颗粒虽与任何其他已知逆转录病毒不同但可在滑液中检测到，很可能是RA发病机制中的一个重要刺激因素。为简化RA中令人困惑的癌基因相互作用事件，我们总结了数据并提出癌基因网络作为类风湿关节滑膜细胞中的致病机制。类似于调节T细胞依赖性途径的“细胞因子网络”，“癌基因网络”大概是RA中主要的T细胞非依赖性途径（图4）。
