Spatiotemporal Progression of Meniscal Degradation

半月板退化的时空进展

• 批准号: 7594913
• 负责人: MARC Elliot LEVENSTON
• 金额: $ 15.8万
• 依托单位: STANFORD UNIVERSITY
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7594913
• 关键词: Address; Applications Grants; Arts; Behavior; Biochemical; Biological Models; Biomechanics; Bos taurus; Cartilage; Cattle; Cells; Clinical; Clinical Research; Collagen; Degenerative polyarthritis; Detection; Development; Diagnosis; Early Diagnosis; Early Intervention; Event; Exhibits; Extracellular Matrix; Future; Goals; Gold; Human; Image; Interdisciplinary Study; Invasive; Joints; Knee; Knee Osteoarthritis; Knowledge; Lesion; Localized; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Meniscus structure of joint; Methods; Modality; Monitor; Musculoskeletal; Operative Surgical Procedures; Play; Postdoctoral Fellow; Property; Proteoglycan; Research; Research Personnel; Research Project Grants; Role; Severities; Signal Transduction; Staging; Surface; Testing; Tissues; Touch sensation; Treatment Effectiveness; clinically relevant; improved; in vitro Model; knee replacement arthroplasty; multidisciplinary; musculoskeletal imaging; novel; parent grant; polysulfated glycosaminoglycan; response; soft tissue; spatiotemporal; two-dimensional; wasting

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.

描述(申请人提供)：半月板退行性变通常与晚期膝关节骨关节炎(OA)的软骨退变有关，但半月板退行性变在膝骨性关节炎的发病和进展之间的关系尚不清楚。半月板撕裂一直被认为是膝关节骨性关节炎的致病因素，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，退行性半月板的改变，无论它们是否撕裂，可能是膝骨性关节炎发生的早期事件。然而，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。这项建议的父母资助(R01AR052861，半月板退化的时空进展)通过使用体外模型系统检查生化和生物力学诱导半月板退化的影响来解决这一知识缺口。到目前为止的结果表明，半月板细胞在白细胞介素I的刺激下积极降解细胞外基质(特别是初级胶原束周围的基质中的蛋白多糖)，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和更早的作用。重要的是，这种蛋白多糖的降解导致组织的功能性生物力学特性迅速而显著地下降。因此，对半月板区域蛋白多糖耗竭的非侵入性检测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，并成为监测早期干预效果的潜在靶点。拟议的研究将涉及一个跨学科的研究团队，该团队在开发新的磁共振成像策略、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方面具有专业知识。该项目的重点将是确定能够识别与组织生物力学受损相关的退行性半月板损伤的MRI成像方式。目标1将包括检测由健康牛半月板的受控酶降解引起的损伤，作为识别最有希望的成像方式的平台。目标2将涉及从全膝关节置换手术中获得的大体完好的半月板的特征。MRI信号在特定区域的变化程度将与硫酸糖胺多糖含量、蛋白多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父母资助的范围，并将为开发新的临床成像策略奠定基础，以非侵入性检测与功能相关的半月板损伤。