Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading

项目概要/摘要： 创伤后骨关节炎（PTOA）影响至少50%的遭受创伤性关节损伤的人，例如 前交叉韧带（ACL）断裂，通常在1-2年内出现症状性关节疼痛 受伤后。在早期阶段调节关节负荷（运动/行走）或卸载（休息/废用）（<7 天）可用于减少引发PTOA的炎症和分解代谢过程。 然而，目前临床上对关节负荷或卸载的建议没有共识， 早期阶段，和损伤后加载/卸载对关节退行性变的影响从来没有 机械地调查。这项研究的总体目标是确定生物力学干预如何 可在关节损伤后用于影响PTOA的发生和进展。拟议的研究将 使用临床相关损伤模型（小鼠中的非侵入性、机械诱导的ACL断裂）和临床 相关的伤后情况（受伤肢体的机械卸载、间歇性重新加载、手术 以确定生物力学疗法对减缓PTOA进展的作用 伤后我们假设，损伤后的卸载将减少炎症，蛋白酶活性， 损伤后早期关节的机械损伤，以及这些早期过程的缓解 将改变PTOA进展相对于正常加载关节的轨迹。我们进一步假设， 与卸载相关的肌肉和骨萎缩将通过间歇性再加载而得到改善， 导致关节退化，并且在卸载一周后对膝关节进行手术重新稳定将 进一步减少长期关节退化，而正常负荷一周后的重新稳定不会 对于改变PTOA的轨迹同样有效。我们将首先确定机械卸载的效果 在早期阶段的炎症和分解代谢过程和长期的关节退化。接下来我们就 确定间歇性再负荷对肌肉质量和强度、软骨下骨结构的影响，以及 长期的关节退化最后，我们将确定手术重新稳定膝关节的效果 在长期关节退化的早期阶段，在正常活动或机械卸载之后。 这些研究将确定是否卸载和其他生物力学治疗在早期损伤后 阶段“暂停”PTOA开发（即，延迟，但不能防止长期关节退化），或者如果他们是 能够减少长期的关节退化。这些研究将使我们能够单独评估 关节卸载、间歇性重新加载和受伤后的手术关节重新稳定，并将提供 对生物力学干预的机械见解，将为后续的临床研究提供信息， 从而优化治疗策略以保持损伤后患者的长期关节健康。

Project Summary/Abstract: Post-traumatic osteoarthritis (PTOA) affects at least 50% of people who sustain a traumatic joint injury such as anterior cruciate ligament (ACL) rupture, with symptomatic joint pain typically developing within 1-2 decades following injury. Modulating joint loading (exercise/walking) or unloading (rest/disuse) in the early phase (<7 days) following injury could be used to decrease inflammation and catabolic processes that initiate PTOA. However, there is currently no clinical consensus on recommendations for joint loading or unloading during the early phase, and the effect of post-injury loading/unloading on joint degeneration has never been mechanistically investigated. The overall goal of this research is to determine how biomechanical interventions can be utilized following joint injury to affect the initiation and progression of PTOA. The proposed studies will use a clinically relevant injury model (non-invasive, mechanically-induced ACL rupture in mice) and clinically relevant post-injury conditions (mechanical unloading of the injured limb, intermittent reloading, surgical restabilization of the joint) to determine the effect of biomechanical therapies for slowing PTOA progression after injury. We hypothesize that unloading following injury will reduce inflammation, protease activity, and mechanical damage in the joint during the early post-injury phase, and that mitigation of these early processes will change the trajectory of PTOA progression relative to normally loaded joints. We further hypothesize that muscle and bone atrophy associated with unloading will be ameliorated with intermittent reloading without leading to joint degeneration, and that surgical restabilization of the knee following one week of unloading will further reduce long-term joint degeneration, while restabilization following one week of normal loading will not be as effective for changing the trajectory of PTOA. We will first determine the effect of mechanical unloading during the early phase on inflammatory and catabolic processes and long-term joint degeneration. Next, we will determine the effect of intermittent reloading on muscle mass and strength, subchondral bone structure, and long-term joint degeneration. Finally, we will determine the effect of surgical restabilization of the knee following normal activity or mechanical unloading during the early phase on long-term joint degeneration. These studies will determine if unloading and other biomechanical treatments during the early post-injury phase “pause” PTOA development (i.e., delay but do not prevent long-term joint degeneration), or if they are able to diminish long-term joint degeneration. These studies will allow us to individually evaluate the effects of joint unloading, intermittent reloading, and surgical joint restabilization following injury, and will provide mechanistic insights into biomechanical interventions that will inform subsequent clinical studies, potentially leading to optimization of therapeutic strategies for preserving long-term joint health of patients following injury.