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（由申请人提供）：半月板变性通常与膝盖晚期骨关节炎（OA）的软骨变性有关，但是膝盖OA发作和膝关节进展之间的关系仍然不清楚。半月板撕裂长期以来一直被认为是膝关节OA的促成因素，这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。但是，最近的各种发现表明，无论是否撕裂，退化性的半月板变化都可能是膝盖OA发展的早期事件。尽管有越来越多的迹象表明无症状的半月板变性的重要性，但目前对有助于半月板变性的机制或半月板病变似乎先于软骨变性的原因相对较少。该提案的父授予（R01AR052861，半月板降解的时空进展）通过检查了使用体外模型系统对半月板降解的生化和生物力学诱导的影响，从而解决了知识的这一差距。迄今为止的结果表明，半月板细胞会积极地降解细胞外基质（尤其是围绕原发性胶原蛋白捆绑包的基质室中的蛋白聚糖），当时由Interleuken-I刺激时，基质金属蛋白酶在半月板脱水中的作用比在半月板脱水量中的作用更大。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急剧降低。因此，表现出蛋白聚糖耗竭的半月板区域的非侵入性检测可以确定机械功能受损的区域，从而为检测早期膝关节变性提供了新的机会，并且是监测早期干预效果的潜在目标。拟议的研究将涉及一个跨学科研究团队，该研究团队在新型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方面具有专业知识。该项目的重点是识别能够识别与组织生物力学受损相关的退行性半月板病变的MRI成像方式。 AIM 1将涉及通过控制健康牛半月板的酶促降解引起的病变，作为识别最有前途的成像方式的平台。 AIM 2将涉及表征宏观完整的人半月板，这些人弯板是从总膝关节塑料中获得的手术废物。将特定区域的MRI信号变化程度与硫酸化的糖胺聚糖含量，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展父授予的范围，并为开发新型临床成像策略的发展奠定基础，以无创检测功能相关的半月板病变。