A role for intrinsic tendon cells in overuse injury

描述(申请人提供)：过度使用损伤和其他肌腱疾病是骨科医学中常见的挑战，导致慢性疼痛、功能障碍，甚至肌腱断裂。大多数慢性肌腱损伤和疾病都被认为是从反复暴露在低强度的力中开始的，这些力对组织造成了显微镜下的“损伤”。然而，重复负荷--即所谓的“过度使用”--在慢性肌腱损伤发病机制中的作用尚不清楚。具体地说，肌腱病是一种在没有炎症的情况下发生退行性变化的情况。在这些情况下，人们推测疲劳的肌腱失去了内源性修复能力。重复的微创伤可能会压倒肌腱细胞修复损伤的能力，甚至刺激它们以一种降解其局部细胞外基质的方式做出反应。持续的重复活动可能会导致损伤的积累，最终破坏肌腱的结构。 由于慢性肌腱损伤被认为始于反复暴露在低强度的力中，我们假设它们是细胞介导的过程(例如，异常修复和/或定向降解)的结果，而不是材料疲劳的结果。我们将在器官培养模型中探索这一假设，在该模型中，肌腱细胞可以在其天然的三维环境中保持。为了区分细胞介导的损伤和仅由材料疲劳引起的损伤，我们首先建立并循环加载失活的肌腱外植体来评估材料损伤。然后，我们将调查循环机械载荷是否会在重要肌腱植入物中引发损伤反应，以及载荷是否小于急性损伤失活肌腱所需的载荷。肌腱损伤阈值较低，提示肌腱细胞在肌腱过度使用损伤的发病机制中起着重要作用。

DESCRIPTION (provided by applicant): Overuse injuries and other tendon disorders represent a common challenge in orthopaedic medicine, resulting in chronic pain, functional disability and even tendon rupture. Most chronic tendon injuries and disorders are believed to start from repeated exposure to low-magnitude forces that 'injure' the tissue microscopically. However, the role of repetitive loading-- so-called 'overuse'-- in the pathogenesis of chronic tendon injury is not well-understood. In particular, tendinosis is a condition where degenerative changes occur in the absence of inflammation. In these cases it is speculated that fatigued tendon loses its endogenous reparative ability. Repetitive microtrauma may overwhelm the ability of tendon cells to repair damage, or even incite them to respond in a manner that is degradative to their local extracellular matrix. Continued repetitive activity may lead to an accumulation of damage that eventually disrupts the structure of the tendon. Because chronic tendon injuries are believed to start from repeated exposure to low-magnitude forces, we hypothesize that they are the result of cell-mediated processes (e.g., aberrant repair and/or directed degradation) rather than material fatigue. We will explore this hypothesis in an organ culture model where tendon cells can be maintained in their native three-dimensional environment. To differentiate between damage that is cell-mediated and damage due to material fatigue alone, we will first establish and then cyclically load a devitalized tendon explant to assess material damage. We will then investigate if cyclic mechanical load will instigate a damage response in vital tendon explants and whether the loads are less than those required to acutely damage devitalized tendon. A role for intrinsic tendon cells in the pathogenesis of tendon overuse injury would be implied by a lower damage threshold in vital tendon.