Spatiotemporal Progression of Meniscal Degradation

半月板退化的时空进展

• 批准号: 7503639
• 负责人: MARC Elliot LEVENSTON
• 金额: $ 29.15万
• 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/7503639
• 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; Endopeptidases; Environmental Risk Factor; Event; Failure; Gender; Goals; Hour; Image; Immunofluorescence Immunologic; In Vitro; Incidence; Inflammatory; Interleukin-1; Interleukins; Joint Instability; Joints; Knee; Knee Osteoarthritis; Lead; Lesion; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Mediating; Meniscus structure of joint; Obesity; Organ; Osteoarthrosis Deformans; Other Finding; Pain; Pathogenesis; Peptide Hydrolases; Play; Population Control; Prevalence; Prevention; Production; Property; Proteoglycan; Proteolytic Processing; Research Personnel; Role; Series; Simulate; Site; Staging; Stimulus; Structure; System; Testing; Thinking; Time; Tissues; aggrecan; aggrecanase; aggrecanase-1; articular cartilage; cytokine; inhibitor/antagonist; insight; novel diagnostics; prevent; programs; protein expression; response; spatiotemporal; therapeutic target

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，纤维软骨半月板变性与晚期膝骨关节炎（OA）中的软骨变性有关，但膝关节 OA 发病和进展中半月板变性之间的关系仍不清楚。长期以来，半月板撕裂一直被认为是膝关节骨关节炎的一个促成因素，主要是由于关节生物力学的变化导致软骨上的机械应力局部增加或减少。然而，最近的各种研究结果表明，退行性半月板变化，无论是否存在撕裂，都可能是特发性膝关节 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，但目前对于导致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知之甚少。 拟议的研究将调查生物化学和生物力学诱导半月板退化的影响。目标 1 将检查外源性白细胞介素-1 (IL-1) 诱导的半月板退化的进展，以检验以下假设：半月板对 IL-1 的加速反应涉及软骨退化中活跃的蛋白水解过程，并且分散在内部（压缩）和外部（张力）区域。目标 2 将检查压缩超负荷引起的半月板降解的进展，以检验半月板外植体的适度压缩超负荷将诱导细胞介导的基质降解的假设，该降解涉及由 IL-1 刺激诱导的相同分解代谢过程。目标 3 将检查聚集蛋白聚糖酶抑制保护半月板基质免遭降解的能力，以检验预防聚集蛋白聚糖消耗将保护胶原蛋白免遭蛋白水解降解的假设。 这些研究将为半月板变性的进展提供重要的新见解，并可能产生新的诊断或治疗靶点来预防或延缓骨关节炎的进展。