Preventing Cartilage Degeneration after Traumatic Injury

描述（由申请人提供）：最简单地说，骨关节炎可以理解为关节软骨的磨损，关节软骨是一种自我修复能力有限的组织。最近的研究结果表明，软骨损伤后进行性降解与特定酶（称为金属蛋白酶）的升高和激活密切相关。除了可能的治疗，关节负荷，如在物理治疗或运动过程中可以影响基质生物合成和降解事件取决于负荷的过程。更好地理解损伤软骨的机械生物学和循环载荷对组织降解的影响是优化软骨退变治疗的重要一步。在本申请中，我们假设循环负荷调节损伤后的组织变性，并影响金属蛋白酶抑制剂的疗效。利用我们实验室最近开发的体外模型系统，我们建议研究每日负荷（固定与低和中等循环压缩）如何影响特定的降解事件以及定义的亚骨折损伤后软骨的治疗。我们的具体目标是：1）确定每日负荷对基质生物合成、细胞因子水平、基质降解、细胞凋亡和生物力学性质的影响;和2）确定在每日负荷存在下基质金属蛋白酶抑制剂（MMPI）对预防基质变性的功效。将通过确定细胞因子水平、金属蛋白酶升高/活化、基质（蛋白聚糖和胶原）损失和降解、基质生物合成、胶原网络完整性（组织肿胀）和软骨中组织生物力学特性（损伤后7天），在分子、细胞和结构水平上测试结局。其意义是双重的，首先是确定损伤软骨的机械生物学，其次是了解机械负荷如何影响治疗性治疗，如使用MMPIs。我们相信这项研究的结果将显著影响创伤性骨关节炎和其他类型关节炎中软骨退化的治疗方法。

DESCRIPTION (provided by applicant): In simplest terms, osteoarthritis can be understood as the wearing away of articular cartilage, a tissue with a limited ability to repair itself. Findings from recent studies suggest that progressive degradation in cartilage after injury is closely related to the elevation and activation of specific enzymes, called metalloproteinases. In addition to possible treatments, joint load such as during physical therapy or exercise can affect matrix biosynthesis and the degradative events depending on the courses of loading. A better understanding of the mechanobiology of injured cartilage and the effects of cyclic loads on tissue degradation is an important step for optimizing the treatments for cartilage degeneration. In this application, we hypothesize that cyclic load modulates tissue degeneration following injury and affects the efficacy of metalloproteinase inhibitors. Taking advantage of an in vitro model system developed recently in our laboratory, we propose to study how daily load (immobilization vs. low and moderate cyclic compression) affects specific degradative events and the treatments of cartilage following defined subfracture injury. Our specific aims are: 1) to determine the effects of daily load on matrix biosynthesis, cytokine level, matrix degradation, cell apoptosis, and biomechanical properties; and 2) to determine the efficacy of matrix metalloproteinase inhibitors (MMPI) on preventing matrix degeneration in the presence of daily load. The outcomes will be tested at the molecular, cellular and structural levels by determining the level of cytokines, elevation/activation of metalloproteinases, matrix (proteoglycan and collagen) loss and degradation, matrix biosynthesis, collagen network integrity (tissue swelling), and tissue biomechanical properties in the cartilage for up to 7 days after injury. The significance is two fold, first to determine the mechanobiology of injured cartilage and second to understand how mechanical load influences therapeutic treatments such as the use of MMPIs. We believe the results of this study will significantly impact the ways to treat cartilage degeneration in traumatic osteoarthritis and other types of arthritis.