Spatiotemporal Progression of Meniscal Degradation

描述（由申请人提供）：半月板退变通常与膝关节晚期骨关节炎（OA）中的软骨退变相关，但半月板退变与膝关节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，退行性膝关节改变，无论是否撕裂，可能是膝关节OA发展的早期事件。尽管越来越多的迹象表明无症状性椎间盘退变的重要性，但是，目前对导致椎间盘退变的机制或椎间盘病变先于软骨退变的原因知之甚少。该提案的母基金（R 01 AR 052861，半月板退化的时空进展）通过使用体外模型系统检查生物化学和生物力学诱导半月板退化的影响来解决这一知识缺口。迄今为止的结果表明，椎间盘细胞积极降解细胞外基质（特别是蛋白多糖的基质室周围的初级胶原束）时，刺激白细胞介素-I，基质金属蛋白酶发挥更大的和更早的作用，椎间盘降解比软骨降解。重要的是，这种蛋白聚糖降解导致组织的功能生物力学性质的快速和显著降低。因此，非侵入性检测表现出蛋白聚糖耗竭的关节区域可以识别机械功能受损的区域，为检测早期膝关节退行性变提供了新的机会，并为监测早期干预措施的有效性提供了潜在的目标。拟议的研究将涉及一个跨学科的研究团队，该团队具有开发新型MRI策略、肌肉骨骼软组织临床成像以及肌肉骨骼软组织生化和生物力学分析的专业知识。本项目的重点是确定能够识别与受损组织生物力学相关的退行性椎间盘病变的MRI成像模式。目标1将涉及检测由健康牛盲肠的受控酶促降解诱导的病变，作为识别最有前途的成像模式的平台。目标2将涉及表征从全膝关节置换术中作为手术废物获得的肉眼可见的完整人体椎间盘。将特定区域的MRI信号变化程度与硫酸化糖胺聚糖含量、蛋白聚糖裂解水平和生物力学特性进行比较。拟议的研究将大大扩大母基金的范围，并将为开发新的临床成像策略奠定基础，以非侵入性检测功能相关的神经病变。

DESCRIPTION (provided by applicant): Meniscal degeneration is typically associated with cartilage 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 stress on the cartilage. However, a variety of recent findings suggest that degenerative meniscal changes, regardless of whether or not they tear, may be an early event in the development of knee OA. Despite the growing indications of the importance of asymptomatic meniscal degeneration, however, relatively little is currently known regarding the mechanisms contributing to meniscal degeneration or the reasons why meniscal lesions appear to precede cartilage degeneration. The parent grant for this proposal (R01AR052861, Spatiotemporal Progression of Meniscal Degradation) addresses this gap in knowledge by examining the effects of biochemical and biomechanical induction of meniscal degradation using in vitro model systems. Results to date indicate that meniscal cells aggressively degrade the extracellular matrix (particularly the proteoglycans in the matrix compartment surrounding the primary collagen bundles) when stimulated by interleuken-I, and that matrix metalloproteinases play a greater and earlier role in meniscal degradation than in cartilage degradation. Importantly, this proteoglycan degradation leads to rapid and dramatic reductions in functional biomechanical properties of the tissue. Noninvasive detection of meniscal regions exhibiting proteoglycan depletion could thus identify regions of impaired mechanical function, providing novel opportunities for detection of early-stage knee degeneration and a potential target for monitoring the efficacy of early interventions. The proposed studies will involve an interdisciplinary research team with expertise in development of novel MRI strategies, clinical imaging of musculoskeletal soft tissues, and biochemical and biomechanical analysis of musculoskeletal soft tissues. The focus of this project will be to identify MRI imaging modalities that are capable of identifying degenerative meniscal lesions associated with impaired tissue biomechanics. Aim 1 will involve detection of lesions induced by controlled enzymatic degradation of healthy bovine menisci as a platform for identifying the most promising imaging modalities. Aim 2 will involve characterization of macroscopically intact human menisci obtained as surgical waste from total knee arthroplasties. The extent of MRI signal changes in specific regions will be compared to sulfated glycosaminoglycan content, levels of proteoglycan cleavage and biomechanical properties. The proposed studies will substantially extend the scope of the parent grant and will lay the groundwork for the development of novel clinical imaging strategies for noninvasive detection of functionally relevant meniscal lesions.