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

• 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
• 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

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： 创伤后骨关节炎（PTOA）至少影响50％的受创伤性关节损伤的人，例如 前交叉韧带（ACL）破裂，有症状的关节疼痛通常在1-2年内出现 受伤后。在早期阶段调节关节载荷（锻炼/步行）或卸载（休息/废除）（<7 几天）受伤后可用于减少启动PTOA的感染和分解代谢过程。 但是，目前尚未就关节加载或卸载的建议达成共识 早期阶段，以及伤害后加载/卸载对关节变性的影响 机械研究。这项研究的总体目标是确定生物力学干预措施 可以在关节损伤后使用以影响PTOA的主动性和进展。拟议的研究将 使用临床上相关的损伤模型（无创机械诱导的小鼠ACL破裂）和临床 相关伤害后情况（受伤的肢体的机械卸载，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PTOA进展减缓的影响 受伤后。我们假设受伤后的卸载将减少感染，蛋白酶活性和 在伤害后阶段，关节的机械损坏，以及这些早期过程的缓解 相对于正常负载的接头，将改变PTOA进展的轨迹。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来改善 导致联合变性，并在卸载一周后膝盖的手术对手 进一步降低长期的联合变性，而在正常负载一周后重新稳定将不会 对于更改PTOA的轨迹同​​样有效。我们将首先确定机械卸载的效果 在炎症和分解代谢过程和长期关节变性的早期阶段。接下来，我们会的 确定间歇性重新加载对肌肉质量和强度，软骨下骨结构以及 长期关节变性。最后，我们将确定膝盖外科手术的效果 在早期的长期关节变性后，在正常活动或机械卸载之后。 这些研究将确定在受伤后早期的卸载和其他生物力学治疗 阶段“暂停” PTOA开发（即延迟但不能防止长期联合变性），或者如果它们是 他们可以减少长期的联合变性。这些研究将使我们能够单独评估 受伤后，关节卸载，间歇性重新加载和手术关节置换，并将提供 对生物力学干预措施的机械洞察力，这些干预措施将为随后的临床研究提供信息，并有可能 导致优化理论策略，以保留受伤后患者的长期联合健康。