Novel Mechanism for Repair of Tendon Fatigue Damage Injuries

修复肌腱疲劳损伤的新机制

• 批准号: 10255875
• 负责人: NELLY Andarawis-Puri
• 金额: $ 47.59万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255875
• 关键词: Address; Adhesions; Area; Biological; Biomechanics; Cell Survival; Cells; Chronic; Clinical; Collagen; Collagen Fiber; Data; Development; Diagnostic; Ensure; Exercise; Exhibits; Extracellular Matrix; Fatigue; Fibronectins; Fluorescence; Generations; Guidelines; ITGA5 gene; Injury; Integrin alpha5beta1; Integrins; Intervention; Laceration; Lead; Mechanics; Modeling; Morphology; Myofibroblast; Outcome; Pathogenesis; Peptides; Phase; Physiological; Population; Process; Publishing; RNA Splicing; Rattus; Role; Rupture; Strenuous Exercise; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Therapeutic; Therapeutic exercise; Time; Translations; Treatment Efficacy; Up-Regulation; Variant; Work; base; crosslink; healing; impaired capacity; in vivo Model; mechanical properties; mechanotransduction; musculoskeletal injury; novel; patellar tendon; repaired; response; restoration; targeted treatment; tendon rupture; therapeutic development; therapy outcome

Tendinopathies are common musculoskeletal injuries that lead to tendon rupture and disuse. Degenerative changes in ruptured tendons suggest that subrupture fatigue damage accumulation from wear and tear is an integral component in the pathogenesis of tendinopathy. Consequently, we have previously developed an in vivo model of sub-rupture fatigue damage accumulation using the rat patellar tendon to investigate the onset and pathogenesis of tendinopathy. We have shown that even just one bout of fatigue loading leads to development of collagen damage kinks and a 20% decrease in stiffness of the tendon that is not recovered out to at least 8- weeks. A major hurdle to progress in management of developing chronic tendinopathies is that the mechanism of tendon repair is unknown, largely because it does not naturally occur. Our previous work investigating the utility of exercise as a therapeutic showed that exercise leads to repair when initiated 2-weeks after onset of sub- rupture fatigue injury but promotes further degeneration when initiated 1-day after sub-rupture fatigue injury. Generation of these two contrasting models (effective therapeutic exercise and detrimental therapeutic exercise of fatigue damaged tendons) will be invaluable to unraveling the mechanisms that drive the response of fatigue damaged tendons to conservative treatment. Interestingly, the main difference in the degenerative versus reparative outcome from therapeutic exercise is the time of initiation even though the fatigue damaged tendons at both timepoints exhibit similar macroscopic mechanical properties. It is therefore critical to determine the biomechanical conditions wherein conservative treatment, such as exercise, will promote repair and not further degeneration. In addition, an increase in population of myofibroblasts and integrin α5 was uniquely associated with repair of fatigue damaged tendons from effective therapeutic exercise leading to generation of a novel mechanistic hypothesis for repair of sub-rupture fatigue damaged tendons. We hypothesize that repair of fatigue damage follows 3-phases. In phase 1, regions of matrix damage are repopulated with tenocytes that have re- established cell-ECM interactions. In phase 2, myofibroblasts are activated in regions of matrix damage, likely driven by integrin α5 and the fibronectin splice variant, FN-EDA. In phase 3, myofibroblasts tension the damage kinks and increase cross-linking. The proposed studies will interrogate our mechanistic hypothesis by evaluating the cell-ECM interactions that evolve over the 2-weeks after onset of injury (Aim 1) and interrogating the role of myofibroblasts in repair of fatigue damage injury (Aim 2). Lastly, the role of integrin α5 (dependent or independent of myofibroblasts) in repair of sub-rupture fatigue injuries will be interrogated (Aim 3). The proposed studies will (A) identify biological and mechanical factors that should be considered prior to initiation of conservative treatment such as exercise, (B) determine the therapeutic potential of myofibroblasts, and (C) identify alternative therapeutic approaches by identifying mechanisms that could be interrogated to drive remodeling and myofibroblast activation.

肌腱病是常见的肌肉骨骼损伤，导致肌腱断裂和废用。退行性 断裂肌腱的变化表明，磨损和撕裂引起的亚断裂疲劳损伤累积是一种 肌腱病发病机制中不可或缺的组成部分。因此，我们以前已经开发了一种体内 使用大鼠髌腱建立亚断裂疲劳损伤累积模型， 肌腱病的发病机制。我们已经表明，即使只是一次疲劳加载， 胶原蛋白损伤扭结和肌腱刚度下降20%，无法恢复到至少8- 周发展中的慢性肌腱病的管理进展的一个主要障碍是， 肌腱修复是未知的，主要是因为它不会自然发生。我们之前的工作是调查 运动作为一种治疗的效用表明，运动导致修复时，开始2周后发病的亚， 断裂疲劳损伤，但促进进一步退化时，开始1天后亚断裂疲劳损伤。 这两种对比模型（有效治疗运动和有害治疗运动）的生成 的疲劳损伤肌腱）将是非常宝贵的解开机制，驱动响应的疲劳 损伤肌腱保守治疗。有趣的是，退行性病变与 治疗性运动的修复结果是开始的时间，即使疲劳损伤了肌腱 在两个时间点表现出相似的宏观机械性能。因此，确定 生物力学条件，其中保守治疗，如运动，将促进修复，而不是进一步 退化此外，肌成纤维细胞和整合素α5的数量增加是唯一相关的 通过有效的治疗锻炼修复疲劳损伤的肌腱， 修复亚断裂疲劳损伤肌腱的机械假说。我们假设疲劳的修复 损害分为三个阶段。在第1阶段，基质损伤区域重新填充有重新形成的腱细胞， 建立细胞-ECM相互作用。在第2阶段，肌成纤维细胞在基质损伤区域被激活，可能是 由整合素α5和纤连蛋白剪接变体FN-EDA驱动。在第3阶段，肌成纤维细胞拉伸损伤 扭结并增加交联。拟议的研究将通过评估来质疑我们的机制假设。 损伤后2周内细胞-ECM相互作用的演变（目的1），并询问 肌成纤维细胞在疲劳损伤修复中的作用（目的2）。最后，整合素α5的作用（依赖性或独立性） 的肌成纤维细胞）修复亚破裂疲劳损伤的作用（目的3）。拟议的研究将 (A)确定在开始保守治疗之前应考虑的生物和机械因素 （B）确定肌成纤维细胞的治疗潜力，和（C）鉴定替代治疗， 通过识别可以被询问以驱动重塑的机制来治疗方法， 肌成纤维细胞活化。