Spatiotemporal Progression of Meniscal Degradation

半月板退化的时空进展

• 批准号: 6963057
• 负责人: MARC Elliot LEVENSTON
• 金额: $ 29.12万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963057
• 关键词: animal tissue; articular cartilage; biomarker; biomechanics; biotransformation; cartilage disorder; cellular pathology; chondrocytes; chondroitin sulfates; early diagnosis; enzyme linked immunosorbent assay; immunofluorescence technique; interleukin 1; knee; osteoarthritis; pathologic process; polymerase chain reaction; proteoglycan; tissue /cell culture; western blottings

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.

描述(申请人提供)：纤维软骨半月板退变长期以来一直与晚期膝关节骨关节炎(OA)的软骨退变有关，但半月板退变在膝骨性关节炎的发病和进展中的关系仍不清楚。半月板撕裂一直被认为是膝关节骨性关节炎的一个因素，主要是由于关节生物力学的改变，导致软骨上的机械应力局部增加或减少。然而，最近的各种发现表明，退行性半月板改变，无论是否有撕裂，可能是特发性膝骨性关节炎发生的早期事件。尽管越来越多的迹象表明无症状半月板退变的重要性，但目前对半月板退变的机制或半月板损伤似乎先于软骨退变的原因知之甚少。 拟议的研究将调查生化和生物力学诱导半月板降解的影响。目的1研究外源性白介素1(IL-1)诱导的半月板降解过程，以验证半月板对IL-1的加速反应涉及软骨降解中活跃的蛋白分解过程，并分布于内(压缩)区和外(张)区。目的2研究半月板受压过载后半月板降解的进展，以验证半月板适度受压过载会导致细胞介导的基质降解的假说，该过程与IL-1刺激所引起的分解代谢过程相同。目的3研究蛋白聚糖酶抑制对半月板基质的保护作用，以验证防止蛋白聚糖耗竭将保护胶原蛋白不被降解的假说。 这些研究将为半月板退行性变的进展提供重要的新见解，并可能导致新的诊断或治疗靶点来预防或延缓OA的进展。