Spatiotemporal Progression of Meniscal Degradation

半月板退化的时空进展

基本信息

批准号：
7761685
负责人：
MARC Elliot LEVENSTON
金额：
$ 28.86万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-05 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7761685
关键词：
Acute Address Age Biochemical Biomechanics Cartilage Catabolic Process Catabolism Cell Death Cell Survival Cells Chondrocytes Chronic Collagen Complex Degenerative polyarthritis Development Diagnosis Early treatment Environmental Risk Factor Event Failure Gender Goals Hour Image Immunofluorescence Immunologic In Vitro Incidence Inflammatory Interleukin-1 Interleukins Joint Instability Joints Knee Osteoarthritis Lead Lesion Magnetic Resonance Imaging Matrix Metalloproteinases Mechanical Stress Mechanics Mediating Meniscus structure of joint Obesity Organ Osteoarthrosis Deformans Pathogenesis Peptide Hydrolases Play Population Control Prevalence Prevention Production Property Proteoglycan Proteolytic Processing Research Personnel Role Series Simulate Site Staging Stimulus Structure System Testing Time Tissues aggrecan aggrecanase aggrecanase-1 articular cartilage cytokine inhibitor/antagonist insight joint destruction knee pain novel diagnostics prevent programs protein expression response spatiotemporal therapeutic target

项目摘要

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（由申请人提供）：长期以来，纤维球纤维弯曲板的变性与膝盖晚期骨关节炎（OA）的软骨变性有关，但是膝盖发作和膝盖进展之间的关系尚不清楚。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，无论是否存在眼泪，变性的半月板变化都可能是特发性膝盖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是软骨变性之前的原因相对较少。拟议的研究将研究半月板降解的生化和生物力学诱导的影响。 AIM 1将检查外源性白介素-L（IL-1）引起的半月板降解的进展，以检验以下假设：对IL-1的加速半月板响应涉及活性的软骨降解中的蛋白水解过程，并且在内部（压缩）和（压缩）和外部（张力）中分散。 AIM 2将检查通过压缩超负荷引起的半月板降解的进展，以检验以下假设：中等压缩的半月板外植体将诱导细胞介导的基质降解，涉及IL-1刺激引起的相同分解代谢过程。 AIM 3将检查脂肪酶抑制保护半月板矩阵免受降解的能力，以检验预防脂肪蛋白消耗将保护胶原蛋白免受蛋白水解降解的假设。这些研究将为半月板变性的发展提供重要的新见解，并可能导致新颖的诊断或治疗靶标，以防止或延迟OA的发展。