ACL Deficiency Modifies Topographical Degradation in Posttraumatic Osteoarthritis

 描述(申请人提供)：创伤是膝骨性关节炎的主要病因之一。除了对关节软骨的钝性冲击外，创伤还经常损害关节内的其他组织，如半月板、前十字韧带(ACL)和软骨下骨。这种损伤会引起一系列的不良事件，导致创伤后骨关节炎(PTOA)的发生和发展。缺乏基于定量成像的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。这个项目的目标是应用几个复杂的和定量的成像参数来确定与PTOA相关的分子和形态水平的特征事件，使用兔模型。中心假设是，与单独的影响或单独的前交叉韧带缺乏相比，前交叉韧带缺乏和创伤同时存在会加速组织退变中的不良事件。在强大的初步数据的指导下，中心假说将通过追求两个具体目标来检验：(1)绘制兔膝关节单次撞击后三个时间点的股骨、胫骨关节软骨和软骨下骨的超微结构和分子/影像生物标志物的地形图；(2)确定单一撞击和前交叉韧带缺乏联合作用对关节软骨和软骨下骨拓扑退化的加速作用。在第一个目标下，关节软骨和软骨下骨的一系列细胞、分子、超微结构和形态的级联降解将在关节表面上以地形绘制，跨不同的结构区以不同的深度依赖，并以高分辨率进行。在第二个目标下，将定量地确定创伤和前交叉韧带缺乏共同作用下的组织降解加速。在这项临床前研究的结论中，一系列能够预测和监测PTOA进展的多学科参数将以高分辨率被识别和量化。该项目具有重要的意义和创新意义，因为它首次将这些先进的参数用于研究前交叉韧带损伤影响下PTOA进展的加速。我们将为理解PTOA的复杂机制奠定坚实的基础。拟议中的项目是一系列研究中的关键一步，预计将导致开发临床和药理学策略，防止组织退化，并允许对简单损伤和创伤造成的复杂损伤进行区别治疗。

 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.