Preventing Cartilage Degeneration after Traumatic Injury

预防外伤后软骨退化

• 批准号: 7207987
• 负责人: Christopher Tung Chen
• 金额: $ 8.46万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7207987
• 关键词: Affect; Anabolism; Animal Model; Animals; Apoptosis; Arthritis; Attenuated; Biological Models; Biomechanics; Cartilage; Cell Death; Cell Proliferation; Cells; Cessation of life; Characteristics; Chondrocytes; Classification; Clinical; Clone Cells; Collagen; Daily; Degenerative polyarthritis; Elevation; Enzymes; Event; Exercise; Growth Factor; Hour; Immobilization; In Vitro; Injury; Interleukin-1; Joints; Laboratories; Lead; Maintenance; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechanics; Medial; Mediating; Metalloproteases; Mitosis; Modeling; Molecular; Motion; Necrosis; Operative Surgical Procedures; Outcome; Outcome Study; Patients; Pharmacological Treatment; Physical therapy; Physiological; Prevention; Process; Property; Proteoglycan; Reporting; Research; Staging; Swelling; Testing; Therapeutic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Tissues; Trauma; Water; articular cartilage; base; collagenase 3; cytokine; day; dosage; improved; in vitro Model; in vivo; inhibitor/antagonist; injured; interest; prevent; repaired; research study

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.

描述(申请人提供)：简单地说，骨性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，损伤后软骨的进行性降解与称为金属蛋白酶的特定酶的升高和激活密切相关。除了可能的治疗外，关节负荷，如在物理治疗或运动期间，可以影响基质生物合成和降解事件，这取决于负荷的过程。深入了解软骨损伤的力学生物学机制和周期性载荷对组织降解的影响，是优化软骨退变治疗的重要步骤。在这个应用中，我们假设周期性负荷调节损伤后的组织退变，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，我们建议研究日常负荷(固定与低和中等循环加压)如何影响特定的降解事件和明确的骨折下损伤后软骨的治疗。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特性的影响；以及2)确定在每日负荷存在的情况下，基质金属蛋白酶抑制剂(MMPI)预防基质退变的效果。结果将通过检测损伤后长达7天的软骨细胞因子水平、金属蛋白酶的升高/激活、基质(蛋白多糖和胶原)的丢失和降解、基质生物合成、胶原网络完整性(组织肿胀)和组织生物力学特性来检验。其意义有两个方面，一是确定受损软骨的机械生物学，二是了解机械负荷如何影响治疗方法，如MMPI的使用。我们相信，这项研究的结果将对创伤性骨关节炎和其他类型关节炎的软骨退行性变的治疗方法产生重大影响。