Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis.
Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis.
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DOI：
10.1016/j.joca.2015.03.027
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发表时间：
2015-11
影响因子：
7
通讯作者：
Plaas A
中科院分区：
文献类型：
--
作者：
Sandy JD;Chan DD;Trevino RL;Wimmer MA;Plaas A
这篇文章的一个主要目的是检验最近可用的人类骨关节炎(OA)关节软骨全基因组表达谱的研究意义。我们认为，当考虑到广泛的早期工作时，这些新颖的数据提供了一个独特的机会，可以重新定位实验系统的设计，使其与临床相关。具体地说，在软骨外植体生物学领域，这将需要对现有范式进行新的评估，以便优化组织来源、细胞因子/生长因子/营养物质添加和发现的生物力学环境的选择。在这一背景下，我们首先讨论了关于潜在的分解代谢介质在骨关节炎病理中的性质和作用的文献，包括来自人骨关节炎软骨的数据、骨关节炎动物模型和体外研究。其次，鉴于IL-1β在这一领域的研究数量和广度，本文的主要重点是对以IL-1β作为模型细胞因子的软骨研究的设计和解释进行批判性分析。第三，从数据驱动的角度(包括对临床样本的全基因组分析、对突变小鼠的研究和临床试验)，得出结论：IL-1β应该被更有可能在OA模型系统中模拟疾病的可溶性介质如IL-17或转化生长因子-β1所取代。我们还讨论了证据表明，早期骨性关节炎的改变可以归因于这些可溶介质的活性，而晚期疾病更多地是由于对剩余软骨的基质和细胞以及其他局部介质分泌细胞的慢性生物力学作用。最后，提供了软骨外植体和软骨细胞体外研究的最新方案(包括使用特定的基因表达阵列)，以促进更多与疾病相关的研究，即细胞因子/生长因子和生物力学对细胞行为的相互作用。
A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that when viewed in the light of extensive earlier work this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1β in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1β has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL-1β should be replaced by soluble mediators such as IL-17 or TGF-β1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines/growth factors and biomechanics on cellular behavior.