Molecular mechanisms of cartilage degeneration in osteoarthritis

关节炎影响了整个澳大利亚人口的15%，60岁以上人群中的50%。到目前为止，最常见的关节疾病是骨关节炎(OA)。骨性关节炎的核心特征之一是覆盖关节骨端的软骨破裂，这是决定长期结果和关节置换手术需求的主要因素。目前还没有阻止或逆转骨性关节炎软骨破坏的治疗方法。这在很大程度上是因为我们对软骨破裂的发生和发展所涉及的分子变化和途径了解得不够深入。强大的新基因组方法允许同时筛选广泛基因的变化，特别是在人类和小鼠的基因组完成测序后。通过将这项新技术应用于骨性关节炎软骨退变的早期阶段，可以发现新基因的作用和参与这一疾病过程的途径。然而，为了研究疾病开始时的变化，必须使用动物关节组织，而不是人类关节组织，因为很难获得症状前期的人类软骨。为了使筛选的基因数量最大化，本研究将使用一种新的手术诱导的小鼠骨性关节炎模型的软骨。我们开发了显微解剖和线性信使核糖核酸扩增方法，以克服这种小动物物种组织可获得性的固有问题。这些研究的成功完成将首次使人们能够确定在早期骨性关节炎中发生的复杂变化。这项研究的一个重要和可能的结果将是识别新的基质蛋白和调节分子，这将为开发新的诊断和治疗方法提供关键信息。

Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the molecular changes and pathways involved in both the onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with tissue availability from this small animal species. Successful completion of these studies will for the first time allow identification of the complex changes that occur in early OA. An important and likely outcome of this research will be identification of novel matrix proteins and regulatory molecules that will provide critical information for the development of new diagnostic and therapeutic approaches to OA.