Proteoglycan metabolism in tendon degeneration

肩袖（RC）肌腱疾病是澳大利亚医疗保健系统的一个巨大负担，也是我们老龄化人口发病率的主要原因。肩关节紊乱是肩关节疼痛最常见的原因，占全科医生所有就诊人数的1.2%。RC病理的患病率随着年龄的增长而增加，到生命的第七个十年达到30-50%，到第九个十年达到惊人的70-80%。虽然大多数病例采用保守治疗，但澳大利亚每年有超过12,000例RC修复手术，患者致力于长期康复。目前还没有专门治疗RC或其他肌腱损伤的药物疗法，许多手术修复在12个月内失败。RC和其他肌腱疾病的有限治疗选择源于缺乏对断裂之前和导致断裂的分子变化的了解。人们认识到，在肌腱蛋白聚糖上的硫酸糖或糖胺聚糖（GAGs）的含量是组织强度的最强预测因子。GAG的积累是人类肌腱撕裂的一个公认的特征。在肌腱断裂之前和导致断裂的蛋白多糖合成和分解的变化尚未明确。我们已经开发了一种新的羊肩肌腱损伤模型，该模型可以诱导模仿人类肩肌腱疾病的局部变性。我们发现特异性蛋白聚糖及其降解酶在早期肌腱疾病中的表达发生了变化。目前的项目将使用该模型与一种新的培养系统和最近开发的转基因小鼠相结合，首次确定随着时间的推移，导致肌腱退化并导致断裂的蛋白聚糖代谢发生的变化。这些研究的成功完成将确定监测疾病进展的生物标志物，并为开发治疗这种使人衰弱的疾病的新治疗策略提供平台。

Rotator cuff (RC) tendon disease is a huge burden on the healthcare system in Australia and a major cause of morbidity in our aging population. Disorders of the RC are the most common cause of shoulder pain, which accounts for 1.2% of all visits to general practitioners. The prevalence of RC pathology increases with age to reach 30-50% by the seventh decade of life and a staggering 70-80% by the ninth. While most cases are treated conservatively, there are over 12,000 RC repair surgeries performed annually in Australia, with patients being committed to a prolonged convalescence. There are no drug therapies to specifically treat RC or other tendon injuries and many surgical repairs fail within 12 months. The limited treatment options for RC and other tendon disorders stems from a lack of knowledge of the molecular changes that precede and lead to rupture. It is recognised that the content of sulphated sugars or glycosaminoglycans (GAGs) on proteoglycans in tendon is the strongest predictor of the tisues strength. Accumulation of GAG is a well-recognised feature of torn tendons in man. The changes in proteoglycan synthesis and breakdown that precede and lead to tendon rupture have not been defined. We have developed a new model of shoulder tendon injury in sheep that induces regional degeneration mimicking that seen in human RC disorders. We have found changes in expression of specific proteoglycans and their degradative enzymes in early tendon disease. The current project will use this model in combination with a novel culture system and recently developed genetically modified mice to determine for the first time the changes that occur over time in proteoglycan metabolism that are responsible for tendon degeneration that leads to rupture. Successful completion of these studies will identify biomarkers to monitor disease progression and a platform for the development of new therapeutic strategies to treat this debilitating disorder.