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: 9889032
• 负责人: YANG XIA
• 金额: $ 43.02万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889032
• 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; 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; Structure; 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; 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冲击外，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) 和软骨下骨。这种损伤会引发一系列连锁不良事件，导致创伤后骨关节炎（PTOA）的发作和进展。缺乏基于成像的定量生物标志物阻碍了对创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，从而改善临床结果。该项目的目标是使用兔子模型，应用几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。中心假设是，与单独影响或单独 ACL 缺陷相比，ACL 缺陷和创伤同时存在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）绘制兔膝单次撞击后股骨和胫骨关节软骨以及软骨下骨超微结构和分子/成像生物标志物的地形退化情况，撞击后延迟三个时间； (2) 确定单一冲击和 ACL 缺陷对关节软骨和软骨下骨拓扑退化的综合影响的加速。在第一个目标下，关节软骨和软骨下骨中一系列细胞、分子、超微结构和形态退化的级联将以高分辨率绘制出关节表面的地形图，跨不同结构区域的深度依赖性。在第二个目标下，将定量确定在创伤和 ACL 缺陷的综合影响下组织退化的加速情况。在这项临床前研究结束时，将以高分辨率识别和量化一系列能够预测和监测 PTOA 进展的多学科参数。该项目既重要又具有创新性，因为它首次使用这些先进参数来研究 ACL 损伤影响下 PTOA 进展的加速情况。我们将为PTOA的复杂机制打下坚实的基础。拟议的项目是连续研究中的关键一步，预计将导致临床和药理学策略的发展，从而防止组织退化，并允许对创伤造成的简单损伤和复杂损伤进行区别治疗。