Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Nat Rev Rheumatol. 2013 Oct;9(10):573-83. doi: 10.1038/nrrheum.2013.121. Epub 2013 Aug 20.
Genetic studies have revealed that most loci associated with osteoarthritis (OA) show ethnic stratification, with limited overlap between Asian and European populations. Consequently, such studies have often focused on particular ethnic groups, with those performed in European cohorts yielding the most replicated associations. As for other common diseases, the OA susceptibility loci mapped to date account for only a fraction of disease heritability. Nevertheless, analysis of these loci could identify biological pathways related to OA pathogenesis. Such an approach is taken in this Review and provides valuable insights into OA aetiology. For example, several of the loci associated with OA contain genes encoding key regulators of skeletogenesis and endochondral ossification. Furthermore, direct and indirect regulation of gene transcription is highlighted as an important factor in this disease. Interestingly, genes encoding structural proteins of the cartilage extracellular matrix do not seem to be a repository for OA susceptibility. Therefore, susceptibility might operate at a regulatory rather than a structural level, which is a potentially promising finding, as the activities of regulators are amenable to therapeutic modulation. Greater clarity will emerge as more association signals are identified; nonetheless, patterns of aetiology are clearly discernible, from a molecular perspective, even with the relatively small number currently available.
遗传研究表明，大多数与骨关节炎（OA）相关的基因座存在种族分层现象，亚洲人和欧洲人群之间的重叠有限。因此，此类研究通常集中在特定的种族群体上，在欧洲队列中进行的研究产生了最多的可重复关联。对于其他常见疾病，迄今为止，OA 易感性基因座映射仅占疾病遗传率的一小部分。然而，对这些基因座的分析可以确定与 OA 发病机制相关的生物学途径。这一方法在本综述中得到了应用，并为 OA 的发病机制提供了有价值的见解。例如，与 OA 相关的一些基因座包含编码骨骼发生和软骨内骨化关键调节剂的基因。此外，基因转录的直接和间接调节被强调为该疾病的一个重要因素。有趣的是，软骨细胞外基质的结构蛋白编码基因似乎不是 OA 易感性的储存库。因此，易感性可能在调节而不是结构水平上起作用，这是一个有希望的发现，因为调节剂的活性可以进行治疗调节。随着更多的关联信号被识别，将更加清晰；尽管如此，从分子角度来看，即使目前可用的数量相对较少，发病机制的模式也很明显。
