ACL Deficiency Modifies Topographical Degradation in Posttraumatic Osteoarthritis

ACL 缺陷改变了创伤后骨关节炎的地形退化

• 批准号: 10380566
• 负责人: YANG XIA
• 金额: $ 39.48万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380566
• 关键词: Acceleration; Adverse event; Affect; Animal Model; Animals; Ankle; Anterior Cruciate Ligament; Architecture; Athletic Injuries; Biochemical; Biological Markers; Blunt Trauma; Cartilage; Chemicals; Clinical; Clinical Pharmacology; Collagen Fibril; Complex; Data; Degenerative polyarthritis; Detection; Development; Diagnostic; Disease; Disease Progression; Enzymes; Etiology; Event; Financial Hardship; Formulation; Foundations; Fourier Transform; Future; Goals; Gold; Health Care Costs; Hip Osteoarthritis; Histopathology; Human; Image; Imaging Device; Individual; Injury; Institutes; International; Intervention; Investigation; Joint Instability; Joints; Knee; Knee Osteoarthritis; Lateral; Lead; Life; Literature; Magnetic Resonance Imaging; Maps; Medial; Meniscus structure of joint; Microscopic; Modeling; Molecular; Monitor; Morphology; Obesity; Oryctolagus cuniculus; Outcome; Pharmacology; Physics; Polarization Microscopy; Prevalence; Procedures; Process; Protocols documentation; Public Health; Recommendation; Reporting; Research; Resolution; Series; Site; Societies; Solid; Stress; Surface; Synovitis; Testing; Time; Tissues; Trauma; Traumatic injury; United States; United States National Institutes of Health; Up-Regulation; X-Ray Computed Tomography; accurate diagnostics; articular cartilage; biomechanical test; bone; cartilage degradation; clinical development; clinical translation; design; disability; effective therapy; imaging biomarker; improved; innovation; ligament injury; microscopic imaging; molecular imaging; multidisciplinary; preclinical imaging; preclinical study; prevent; public health relevance; quantitative imaging; subchondral bone; tissue degeneration; tool

 DESCRIPTION (provided by applicant): Trauma is one of the leading etiologic factors for knee osteoarthritis. In addition to blunt impact to articular cartilage, trauma often damages other tissues in the joint, such as meniscus, anterior cruciate ligament (ACL), and subchondral bone. Such damage can introduce a cascading series of adverse events that leads to the onset and progression of posttraumatic osteoarthritis (PTOA). A lack of quantitative imaging-based biomarkers is preventing an accurate assessment of early tissue degradation after traumatic injury. The long-term goal of our research is to apply the imaging-based biomarkers to detect the early degradation of cartilage and subchondral bone during the progression of osteoarthritis, so that clinical outcomes can be improved. The objective in this project is to apply several sophisticated and quantitative imaging parameters to determine the signature events at the molecular and morphological levels associated with PTOA, using a rabbit model. The central hypothesis is that a simultaneous presence of ACL-deficiency and trauma accelerates the adverse events in tissue degeneration when compared to impact alone or ACL-deficiency alone. Guided by strong preliminary data, the central hypothesis will be tested by pursuing two specific aims: (1) Map the topographical degradations of ultrastructure and molecular/imaging biomarkers in both femoral and tibial articular cartilage and subchondral bone after a single impact in rabbit knee, at three time delays after the impact; and (2) Determine the acceleration of the combined effect of single impact and ACL-deficiency on the topological degradations in articular cartilage and subchondral bone. Under the first aim, a cascade series of cellular, molecular, ultrastructural and morphological degradation in both articular cartilage and subchondral bone will be mapped out topographically over the joint surface, depth-dependently across different structural zones, and at high resolutions. Under the second aim, the acceleration of tissue degradation under the influence of the combined effect of both trauma and ACL-deficiency will be determined quantitatively. At the conclusion of this preclinical study, a se of multidisciplinary parameters that have the ability to predict and monitor PTOA progression will be identified and quantified at high resolution. This project is both significant and innovative, because it puts these advanced parameters to use, for the first time, to investigate the acceleration of PTOA progression under the influence of ACL damage. We will gain a solid foundation on the complex mechanism in PTOA. The proposed project is the critical step in a continuum of research that is expected to lead to the development of clinical and pharmacological strategies that will forestall the tissue degradation and allow differential treatments for simple damage vs. complex damages by trauma.

 描述（由适用提供）：创伤是膝盖骨关节炎的主要病因因素之一。除了对关节软骨的钝性影响外，创伤还经常损害关节的其他时间，例如半月板，前交叉韧带（ACL）和软骨下骨。这种损害会引入一系列级联的不良事件，从而导致创伤后骨关节炎（PTOA）的发作和进展。缺乏基于定量成像的生物标志物是防止对创伤性损伤后早期组织降解的准确评估。我们研究的长期目标是应用基于成像的生物标志物来检测骨关节炎进展过程中软骨和软骨下骨的早期降解，以便可以改善临床结果。该项目的目的是使用兔模型应用几个复杂和定量成像参数来确定与PTOA相关的分子和形态学水平的签名事件。中心假设是，与单独撞击或单独使用ACL缺陷相比，简单的ACL缺乏和创伤的存在加速了组织变性的不良事件。在强有力的初步数据的指导下，将通过追求两个具体目的来测试中心假设：（1）在股骨和胫骨膝盖的单个冲击后，在股骨和下中性骨骼的股骨和胫骨下骨上的超微结构和分子/成像生物标志物的地形降解，在兔子膝盖，三个时间后三个时间造成影响。 （2）确定单个撞击和ACL缺陷对关节软骨和软骨下骨拓扑降解的综合作用的加速。在第一个目标下，关节软骨和软骨下骨中的一系列细胞，分子，超微结构和形态降解都将在关节表面上绘制在地形上，并在不同的结构区域以及高分辨率下深度依赖性。在第二个目标下，将在数量上确定创伤和ACL缺乏效率的组合作用的影响下组织降解的加速。在这项临床前研究的结论中，将在高分辨率下识别和量化具有预测和监测PTOA进程的多学科参数的SE。该项目既重要又创新，因为它使这些高级参数首次使用在ACL损伤的影响下研究PTOA进展的加速。我们将在PTOA中的复杂机制上获得坚实的基础。拟议的项目是一项连续研究的关键步骤，预计会导致临床和药物策略的发展，该策略将阻止组织降解，并允许对简单伤害与创伤的复杂损害进行差异处理。