ACL Deficiency Modifies Topographical Degradation in Posttraumatic Osteoarthritis

 描述（由申请人提供）：创伤是膝关节骨关节炎的主要病因之一。除了对关节软骨的钝性冲击之外，创伤还经常损伤关节中的其他组织，例如半月板、前交叉韧带（ACL）和软骨下骨。这种损伤可能会引起一系列级联的不良事件，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阻碍了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，从而改善临床结局。在这个项目中的目标是应用几个复杂的和定量的成像参数，以确定在分子和形态学水平与PTOA的签名事件，使用兔模型。中心假设是，与单独的撞击或单独的ACL缺陷相比，同时存在ACL缺陷和创伤加速了组织变性中的不良事件。在强有力的初步数据的指导下，将通过追求两个具体目标来检验中心假设：（1）绘制兔膝关节单次撞击后股骨和胫骨关节软骨和软骨下骨中的超微结构和分子/成像生物标志物在撞击后三个时间延迟时的局部降解图;（2）确定单次撞击和ACL缺陷的联合作用对关节软骨和软骨下骨的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中的细胞、分子、超微结构和形态学降解的级联系列将在关节表面上以高分辨率绘制出地形图，在不同的结构区中以深度依赖性绘制。在第二个目标下，将定量确定在创伤和ACL缺陷两者的联合作用的影响下组织降解的加速。在这项临床前研究结束时，将以高分辨率确定和量化一系列能够预测和监测PTOA进展的多学科参数。该项目具有重要意义和创新性，因为它首次使用这些先进的参数来研究ACL损伤影响下PTOA进展的加速。从而为PTOA复杂机理的研究打下坚实的基础。拟议的项目是连续研究的关键一步，预计将导致临床和药理学策略的发展，这些策略将阻止组织降解，并允许对创伤造成的简单损伤与复杂损伤进行差异化治疗。

 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.