Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis
Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis
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DOI：
10.1002/art.22174
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Bartnik, Eckart
中科院分区：
文献类型：
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作者：
Aigner, Thomas;Fundel, Katrin;Bartnik, Eckart
Objective.尽管近几十年来进行了许多研究，但对骨关节炎（OA）的主要发病机制（包括OA软骨退变期间发生的基因改变）了解甚少，并且没有改善疾病的治疗方法。因此，本研究的目的是寻找差异表达的疾病相关基因和潜在的治疗靶点。这项调查包括一个大型的基因表达谱研究的基础上进行的78个正常和疾病的样本，使用定制的互补DNA阵列覆盖超过4,000个基因。发现了许多差异表达的基因，包括合成代谢和分解代谢基质基因的预期上调。特别是，重要的氧化防御基因，即，超氧化物歧化酶2和3以及谷胱甘肽过氧化物酶3的基因是显著的。这表明对细胞和基质的持续氧化应激是OA的一个主要潜在发病机制。此外，基因参与细胞的表型稳定性，这是一个功能，大大减少在OA软骨，似乎被抑制。我们的研究结果提供了OA软骨基因改变的参考数据集，重要的是，指出了OA疾病过程中发生的中枢细胞生物学改变的主要机制。这些结果确定了可以在寻找治疗干预措施中进一步研究的分子靶点。
Objective. Despite many research efforts in recent decades, the major pathogenetic mechanisms of osteoarthritis (OA), including gene alterations occurring during OA cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. The present study was therefore initiated in order to identify differentially expressed disease-related genes and potential therapeutic targets.Methods. This investigation consisted of a large gene expression profiling study performed based on 78 normal and disease samples, using a custom-made complementary DNA array covering > 4,000 genes.Results. Many differentially expressed genes were identified, including the expected up-regulation of anabolic and catabolic matrix genes. In particular, the down-regulation of important oxidative defense genes, i.e., the genes for superoxide dismutases 2 and 3 and glutathione peroxidase 3, was prominent. This indicates that continuous oxidative stress to the cells and the matrix is one major underlying pathogenetic mechanism in OA. Also, genes that are involved in the phenotypic stability of cells, a feature that is greatly reduced in OA cartilage, appeared to be suppressed.Conclusion. Our findings provide a reference data set on gene alterations in OA cartilage and, importantly, indicate major mechanisms underlying central cell biologic alterations that occur during the OA disease process. These results identify molecular targets that can be further investigated in the search for therapeutic interventions.