Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading

通过关节卸载来改变创伤后骨关节炎的进展

基本信息

批准号：
9896699
负责人：
Blaine A. Christiansen
金额：
$ 48.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896699
关键词：
Affect Arthralgia Articular Range of Motion Atrophic Biological Response Modifier Therapy Biomechanics Bone Resorption Bone Spur Bone structure Catabolic Process Cell Death Clinical Clinical Research Consensus Data Degenerative polyarthritis Development Disease Exercise Gait Goals Health Hindlimb Suspension Hour Individual Inflammation Inflammation Process Inflammatory Injury Intervention Joint Laxity Joints Knee Lead Life Mechanics Modeling Moderate Activity Modification Mus Muscle Muscular Atrophy Operative Surgical Procedures Outcome Pain management Patients Peptide Hydrolases Phase Population Process Recommendation Replacement Arthroplasty Research Rest Therapeutic Time Walking anterior cruciate ligament injury anterior cruciate ligament rupture articular cartilage bone bone preservation cartilage degradation clinically relevant injured insight intervention effect joint destruction joint injury joint loading limb injury muscle form muscle strength preservation prevent rehabilitation strategy repaired sham surgery subchondral bone treatment strategy

项目摘要

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.

项目摘要/摘要：至少 50% 遭受创伤性关节损伤的人患有创伤后骨关节炎 (PTOA)，例如前十字韧带 (ACL) 断裂，症状性关节疼痛通常在 1-2 十年内出现受伤后早期调节关节负荷（运动/行走）或卸载（休息/废用）（<7）损伤后几天）可用于减少引发 PTOA 的炎症和分解代谢过程。然而，目前对于关节加载或卸载期间的建议尚未达成临床共识。早期阶段，损伤后加载/卸载对关节退化的影响从未被研究过。这项研究的总体目标是确定如何进行生物力学干预。可以在关节损伤后使用来影响 PTOA 的发生和进展。使用临床相关损伤模型（非侵入性机械诱导小鼠 ACL 断裂）并在临床上相关的损伤后状况（受伤肢体的机械卸载、间歇性重新加载、手术关节的重新稳定）以确定生物力学疗法对减缓 PTOA 进展的效果我们认为受伤后卸载会减少炎症、蛋白酶活性和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 相对于正常负载关节的进展轨迹我们进一步研究了这一点。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，而无需导致关节退化，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。我们首先确定机械卸载的效果。接下来，我们将在炎症和分解代谢过程以及长期关节退化的早期阶段进行研究。确定间歇性重新加载对肌肉质量和力量、软骨下骨结构的影响，以及最后，我们将确定膝关节手术重新稳定的效果。在长期关节退化的早期阶段进行正常活动或机械卸载后。这些研究将确定在受伤后早期是否进行卸载和其他生物力学治疗阶段“暂停”PTOA 发育（即延迟但不阻止长期关节退化），或者如果这些研究将使我们能够单独评估关节退化的影响。关节卸载、间歇性重新加载以及受伤后关节重新稳定手术，并将提供对生物力学干预措施的机制见解将为后续临床研究提供信息，可能从而优化治疗策略，以保持受伤后患者的长期关节健康。