Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading

项目摘要/摘要： 创伤后骨关节炎(PTOA)至少影响50%遭受创伤性关节损伤的人，例如 前十字韧带(ACL)断裂，通常在1-20年内出现症状性关节疼痛 在受伤之后。在早期阶段(&lt；7)调整关节负荷(锻炼/步行)或卸载(休息/停用) 天)可以用来减少炎症和引发PTOA的分解代谢过程。 然而，目前还没有临床共识的建议联合装卸期间 早期阶段，损伤后加卸载对关节退变的影响从来没有 从机械上进行调查。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的启动和进展。拟议的研究将 使用临床相关的损伤模型(非侵入性、机械诱导的小鼠前交叉韧带断裂)和临床 受伤后的相关情况(受伤肢体机械卸载、间歇性重新加载、手术 关节再稳定)，以确定生物力学疗法减缓PTOA进展的效果 受伤后。我们假设，损伤后卸货将减少炎症，蛋白酶活性，并 损伤后早期阶段关节的机械损伤，以及这些早期过程的缓解 将改变相对于正常负荷关节的PTOA进展轨迹。我们进一步假设 与卸载相关的肌肉和骨骼萎缩将通过间歇性重新加载得到改善，而不是 导致关节退变，在卸货一周后手术重新稳定膝关节将 进一步减少长期关节退变，而正常负荷一周后重新稳定不会 同样有效地改变了PTOA的轨迹。我们将首先确定机械卸货的效果 早期对炎症和分解代谢过程及长期关节退变有影响。接下来，我们将 确定间歇性负荷对肌肉质量和力量、软骨下骨结构和 长期关节退行性变。最后，我们将确定膝关节手术再稳定的效果。 术后早期正常活动或机械卸载，长期关节退变。 这些研究将确定在损伤后早期是否进行卸载和其他生物力学治疗 “暂停”PTOA发展阶段(即，延迟但不阻止长期关节退变)，或如果它们是 能够减少长期的关节退行性变。这些研究将使我们能够单独评估 损伤后的关节卸载、间歇性再加载和外科关节再稳定，并将提供 对生物力学干预措施的机械性见解，可能会为后续的临床研究提供信息 从而优化治疗策略，以保护受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.