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[翻译]关节炎：wnt通路出了什么问题？
Date: 2005-06-23
关节炎：wnt通路出了什么问题？
细胞信号蛋白wnt，其与胚胎发育和癌症有关。并且对风湿性关节炎和骨关节炎都有促进作用。Nakamura等人发表于《美国病理学》杂志05年第七期的文章Expression profiles and functional analyses of Wnt-related genes in human joint disorders》（在人关节紊乱症中wnt相关基因的表达谱及功能分析）。
Wnt为人所熟知是因为其原癌基因的身份，因为wnt的破坏可导致多种机体内癌症的发作。比如结肠癌，肺癌和乳腺癌等。然而越来越多的证据说明它于风湿性关机炎有关。目前缺乏在关节炎发展过程中对整个wnt基因家族的综合分析。
日本长野Shinshu大学医学院的研究者研究了wnt基因家族的19名成员，精确的确定了这些基因参与了关节炎疾病之中。
这项广泛的研究是在Shigeyuki Wakitani博士领导下进行的，他是Shinshu大学医学院矫形外科的助理教授。该研究检验了来自风湿性关节炎或骨关节炎而进行全膝置换病人以及无关节炎损伤的健康人的关节组织。
通过使用了几个分子生物学方法，Wakitani的小组鉴定得知wnt－7b和－10a在关节炎膝组织中明显上调。然而蛋白表达研究揭示近wnt－7b在风湿性关节中产生。大部分蛋白定位在滑膜（或关节里侧）。少数定位在软骨成骨中。另外强烈的wnt－7b表达以很高的频率与高炎症区域相关。
作者还比较了来自关节炎和正常关节的初级软骨和滑液细胞以揭示炎症因子是否来自这些细胞。骨关节炎于对照并无不同，初级风湿性关节炎细胞中TNF-a, IL-1ß and IL-6的表达水平比对照高2-4倍。重要的是当正常细胞被设计表达wnt－7b的时候，这一效应可在正常细胞中复制，表明了wnt－7b在风湿性关节炎炎症反应中的重要性。
以上的发现证实了wnt－7b在关节炎发展过程中的角色。风湿性关节炎表现出比如滑膜发炎，软骨成骨缺乏，骨关节炎表现出关节空间收缩，缺乏保护性软骨，以及骨囊肿或骨赘的产生。关节炎疾病的种种表现表明了类型上的不同。
有趣的是wnt－7b在疾病发生处被强烈上调，这主要发生在滑膜处，另外在另外在软骨，骨赘处也有发现。wnt－7b常在炎症区域高表达并引起炎症反应这一发现与风湿性关节炎的炎症特征相符。
共同作者Yukio Nakamura是Shinshu大学医学院的矫形外科医生。他已经研究了引起严重关节变性疾病的wnt相关基因的生物学活性和信号通路。
大多数关于wnt－7b的研究比如功能获得和功能缺失研究给了我们这样的线索：wnt－7b在风湿性关节炎中是一个重要的疾病生物学因素。未来的研究将调查wnt和它信号通路其它成员在风湿性关节变性中的角色。在关节炎发展过程中Wnt信号通路的未来展示将提供给更多关节炎受害者未来的治疗方法。
原文：http://www.sciencedaily.com/releases/2005/06/050622131440.htm
Arthritis: What Wnt Wrong?
The cellular signaling protein Wnt, which is involved in embryonic development and cancer, contributes to disease progression of both rheumatoid arthritis and osteoarthritis. The article by Nakamura et al., "Expression profiles and functional analyses of Wnt-related genes in human joint disorders," appears in the July issue of The American Journal of Pathology and is accompanied by a commentary.
Wnt is best known as a proto-oncogene because its disruption can lead to cancer in various organs such as colon, lung, and breast. However, mounting evidence also points to its involvement in arthritic joint disease. Comprehensive analysis of the entire Wnt gene family in the progression of arthritis has been lacking until now.
Researchers at Shinshu University School of Medicine in Nagano, Japan, examined 19 members of the Wnt gene family to determine exactly which of these genes were involved in arthritic joint disease. This extensive study, performed under the direction of Dr. Shigeyuki Wakitani, who is an assistant professor at the Department of Orthopedic Surgery, Shinshu University School of Medicine, examined joint tissue from patients who underwent total knee replacement for rheumatoid arthritis (RA), osteoarthritis (OA), or non-arthritic injury.
Using several molecular methods, Wakitani's group identified Wnt-7b and -10a as genes that were significantly upregulated in the arthritic knee tissues. However, protein expression studies revealed that only Wnt-7b was produced in arthritic joints, with strong protein localization to the synovium (or joint lining) and weak localization to cartilage and bone. In addition, strong Wnt-7b expression most frequently correlated with areas of high inflammation.
The authors also examined whether inflammatory cytokines were produced in primary cartilage and synovial cells from arthritic versus normal joints. While OA cells did not differ from controls, primary RA cells produced TNF-a, IL-1ß and IL-6 at levels 2- to 4-fold above controls. Importantly, this effect could be replicated in normal cells when they were engineered to express Wnt-7b, demonstrating the importance of Wnt-7b in the inflammatory response of RA.
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作者:admin@医学,生命科学 2011-03-25 05:15
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