Spatiotemporal Progression of Meniscal Degradation

描述（由申请人提供）：半月板变性通常与膝关节晚期骨关节炎（OA）的软骨变性相关，但半月板变性在膝关节OA发病和进展中的关系尚不清楚。半月板撕裂长期以来被认为是导致膝关节OA的一个因素，主要是由于关节生物力学的变化导致软骨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，退行性半月板改变，无论是否撕裂，都可能是膝关节OA发展的早期事件。尽管越来越多的迹象表明无症状半月板变性的重要性，然而，目前对半月板变性的机制或半月板病变出现在软骨变性之前的原因所知相对较少。本提案的母基金（R01AR052861，半月板降解的时空进展）通过使用体外模型系统检查半月板降解的生化和生物力学诱导效应，解决了这一知识空白。迄今为止的研究结果表明，当受到白细胞介素- 1的刺激时，半月板细胞会积极地降解细胞外基质（特别是围绕初级胶原束的基质室中的蛋白多糖），并且基质金属蛋白酶在半月板降解中比在软骨降解中发挥更大、更早的作用。重要的是，这种蛋白聚糖降解导致组织功能生物力学特性的快速和显著降低。因此，无创检测半月板区域的蛋白多糖耗损可以识别机械功能受损的区域，为早期膝关节退变的检测提供了新的机会，并为监测早期干预的效果提供了潜在的目标。拟议的研究将涉及一个跨学科的研究团队，其专长是开发新的MRI策略，肌肉骨骼软组织的临床成像，以及肌肉骨骼软组织的生化和生物力学分析。本项目的重点将是确定能够识别与受损组织生物力学相关的退行性半月板病变的MRI成像模式。目的1将涉及检测由健康牛半月板受控酶降解引起的病变，作为确定最有前途的成像方式的平台。目的2将涉及从全膝关节置换术中获得的外科废物的宏观完整的人类半月板的特征。MRI信号在特定区域的变化程度将与磺化糖胺聚糖含量、蛋白聚糖裂解水平和生物力学性质进行比较。拟议的研究将大大扩展父母资助的范围，并将为开发用于功能相关半月板病变的无创检测的新型临床成像策略奠定基础。

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.