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: 9228320
• 负责人: YANG XIA
• 金额: $ 44.35万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228320
• 关键词: Acceleration; Adverse event; Affect; Animal Model; Animals; Ankle; Anterior Cruciate Ligament; Architecture; Athletic Injuries; Biochemical; Biological Markers; Biomechanics; Blunt Trauma; Cartilage; Chemicals; Clinical; Clinical Pharmacology; Collagen Fibril; Complex; Data; Degenerative polyarthritis; Detection; Development; Diagnostic; Disease; Disease Progression; Enzymes; Etiology; Event; 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; articular cartilage; base; bone; cartilage degradation; clinical development; clinical translation; design; disability; effective therapy; imaging biomarker; improved; innovation; ligament injury; microscopic imaging; molecular imaging; multidisciplinary; pre-clinical; preclinical study; prevent; public health relevance; quantitative imaging; subchondral bone; therapy development; 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（由申请人提供）：创伤是膝骨关节炎的主要病因之一，除了对关节软骨的钝性影响外，创伤还经常损伤关节中的其他组织，例如半月板、前十字韧带 (ACL) 和软骨下组织。这种损伤会导致一系列连锁不良事件，导致创伤后骨关节炎（PTOA）的发生和进展。生物标志物阻碍了对创伤性损伤后早期组织退化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退化，以便临床结果。该项目的目标是使用兔子模型应用多种复杂的定量成像参数来确定与 PTOA 相关的分子和形态水平的特征事件。与单独的影响或单独的 ACL 缺陷相比，创伤会加速组织退化的不良事件。在强有力的初步数据的指导下，中心假设将通过追求两个具体目标进行检验：（1）绘制超微结构和分子/的地形退化图。对兔膝进行单次撞击后，在撞击后延迟三个时间对股骨和胫骨关节软骨以及软骨下骨中的生物标志物进行成像；(2)确定单次撞击和软骨下骨的联合效应的加速度； ACL 缺陷对关节软骨和软骨下骨拓扑退化的影响 在第一个目标下，关节软骨和软骨下骨的一系列细胞、分子、超微结构和形态退化将在关节表面、深度上绘制出来。在高分辨率下，在不同的结构区域中，在创伤和 ACL 缺陷的综合影响下，组织退化将加速。在这项临床前研究结束时，将确定并以高分辨率量化一系列能够预测和监测定量 PTOA 进展的多学科参数，该项目既重要又具有创新性，因为它将这些先进的参数运用到了临床研究中。首次用于研究 ACL 损伤影响下 PTOA 进展的加速情况，我们将为 PTOA 的复杂机制奠定坚实的基础，该项目是预期连续研究的关键一步。带领开发临床和药理学策略，防止组织退化，并允许对创伤引起的简单损伤和复杂损伤进行不同的治疗。