Spatiotemporal Progression of Meniscal Degradation

描述（由申请人提供）：长期以来，纤维软骨韧带的退化与膝关节晚期骨关节炎（OA）中的软骨退化相关，但韧带退化与膝关节OA发作和进展之间的关系尚不清楚。半月板撕裂长期以来被认为是膝关节OA的一个促成因素，主要是由于关节生物力学的变化导致软骨上机械应力的局部增加或减少。然而，最近的各种研究结果表明，无论是否存在撕裂，退行性膝关节改变可能是特发性膝关节OA发展的早期事件。尽管越来越多的迹象表明无症状半月板退行性变的重要性，但目前对导致半月板退行性变的机制或半月板损伤出现在软骨退行性变之前的原因知之甚少。 拟议的研究将调查生物化学和生物力学诱导的生物降解的影响。目的1将检查由外源性白细胞介素-1（IL-1）诱导的软骨降解的进展，以检验对IL-1的加速的软骨应答涉及在软骨降解中活跃的蛋白水解过程并且分散在内部（压缩）和外部（张力）区两者中的假设。目的2将检查由压缩过载诱导的椎间盘降解的进展，以检验以下假设：椎间盘外植体的中度压缩过载将诱导细胞介导的基质降解，涉及与IL-1刺激诱导的相同的分解代谢过程。目的3将检查聚集蛋白聚糖酶抑制剂保护胶原基质免于降解的能力，以检验防止聚集蛋白聚糖耗尽将保护胶原免于蛋白水解降解的假设。 这些研究将为半月板退行性变的进展提供重要的新见解，并可能产生新的诊断或治疗靶点来预防或延缓OA的进展。

DESCRIPTION (provided by applicant): Degeneration of the fibrocartilaginous menisci has long been associated with chondral degeneration in advanced osteoarthritis (OA) of the knee, but the relationship between meniscal degeneration in the onset and progression of knee OA remains unclear. Meniscal tears have long been recognized as a contributing factor to knee OA, primarily due to changes in joint biomechanics that result in local increases or decreases in the mechanical stresses on the cartilage. However, a variety of recent findings suggest that degenerative meniscal changes, regardless of whether or not tears are present, may be an early event in the development of idiopathic knee OA. Despite the growing indications of the importance of asymptomatic meniscal degeneration, relatively little is currently known regarding the mechanisms contributing to meniscal degeneration or the reasons why meniscal lesions appear to precede cartilage degeneration. The proposed studies will investigate the effects of biochemical and biomechanical induction of meniscal degradation. Aim 1 will examine the progression of meniscal degradation induced by exogenous Interleukin-l (IL-1) to test the hypothesis that the accelerated meniscal response to IL-1 involves proteolytic processes active in cartilage degradation and is dispersed throughout both inner (compression) and outer (tension) zones. Aim 2 will examine the progression of meniscal degradation induced by compressive overload to test the hypothesis that moderate compressive overload of meniscal explants will induce cell-mediated matrix degradation involving the same catabolic processes induced by IL-1 stimulation. Aim 3 will examine the ability of aggrecanase inhibition to protect the meniscal matrix from degradation to test the hypothesis that prevention of aggrecan depletion will protect the collagen from proteolytic degradation. These studies will provide important new insights into the progression of meniscal degeneration and could lead to novel diagnostic or therapeutic targets to prevent or delay the progression of OA.