CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Optimizing the Host Environment for Intra-articular Osteoarthritis Therapies

由于关节的影响，骨关节炎在美国军人和退伍军人中非常普遍 创伤和过度使用伤害。它的社会经济影响是巨大的，估计每年接近600亿美元， 而且目前还没有治疗疾病的方法。协作计划的总体目标是开发一种 治疗创伤后骨关节炎(PTOA)，将减轻疼痛和改善功能。我们假设 PTOA是由不良适应修复反应引起的，包括激活促炎通路 先天免疫，进而导致疼痛、功能丧失和结构衰退。本计划针对的是 通过两个高度整合的目标进行假说：(1)开发创新的非药理学和关节内 抑制局部疼痛和炎症的治疗，以及(2)优化基于间充质干细胞(MSC)的治疗 重建受损关节的治疗方法。项目5的目标是确定基于实际证据的 减少PTOA疼痛和提高关节内治疗疗效的干预措施 退伍军人特定健康状况的动物模型。在这一领域取得进展的一个主要障碍是发展 解决慢性PTOA炎症和阻止疾病结构性进展的治疗方法。 很可能需要综合治疗方法来克服这一障碍，并开发出安全和 对退伍军人的有效治疗。我们提议的研究将通过确定温和程度来解决这一未得到满足的需求 运动疗法和关节内皮质类固醇疗法(IA-CST)在 联合改变关节内“宿主环境”的分子和结构条件 它可以减轻疼痛，提高以细胞为基础的PTOA疗法的疗效。这个项目的基本原理是确定 提高疾病疗效和缓解疼痛的非手术干预修改OA疗法将 大大提高了它们的成本效益和临床实施的途径。我们假设这是温和的 运动疗法将通过减少关节炎症来提高关节内OA治疗的疗效， 逆转IA-CST的促分解代谢作用，挽救负面影响的表观遗传变化 自体和异体干细胞疗法。我们测试这一假设的方法的一个关键方面是使用 年龄较大(6-12个月)的高脂饮食诱导的肥胖小鼠。这些小鼠的许多临床特征与 最需要OA治疗的退伍军人群体，他们年龄较大，肥胖，并患有代谢综合征- 相关的并存。该项目利用我们在使用这种临床前动物模型方面的专业知识 学习骨性关节炎的病理生理学。我们将在这些小鼠中使用失稳的内侧半月板PTOA模型 完成三个具体目标。对于每个目标，我们将确定内部和联合的影响 关节CST(曲安奈德)和轻度跑步机运动的目的1)关节结构变化， 炎症和疼痛相关的PTOA功能结果，目的2)关节组织表位转录组的变化 (RNAseq，DNA甲基化)和自体干细胞软骨形成潜力，以及目标3)联合结构和 关节内脂肪来源干细胞(ADSC)治疗后的功能结果。成功完成 这些目标将：1)确定温和运动的有效性，以对抗IA-CST的促分解代谢效应 并扩大疼痛和功能的改善，2)确定运动和IA-CST如何 调节干细胞的软骨生成潜力，以及3)确定运动和IA-CST如何改善短期疼痛 和结构结果使用关节内干细胞为基础的PTOA治疗。这一知识预计将 通过优化联合环境以支持干细胞和骨移植来提高未来PTOA治疗的疗效 以组织工程为基础的再生医学策略。

Osteoarthritis (OA) is highly prevalent in U.S. military service members and Veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is substantial, estimated to approach $60 billion per year, and no disease-modifying treatments exist. The overall goal of the collaborative Program is to develop a treatment for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. We hypothesize that PTOA is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline. This Program address the hypothesis through two highly-integrated aims: (1) developing innovative non-pharmacologic and intra-articular therapies inhibiting local pain and inflammation, and (2) optimizing mesenchymal stem cell (MSC)-based therapies for reconstruction of the damaged joint. The goal of Project 5 is to identify pragmatic evidence-based interventions that reduce PTOA pain and increase the efficacy of intra-articular therapies using a pre-clinical animal model of Veteran-specific health conditions. A major barrier to progress in the field is developing therapeutic approaches that resolve chronic PTOA inflammation and stop the structural progression of disease. It is likely that combined therapeutic approaches will be required to overcome this barrier and develop safe and effective treatments for Veterans. Our proposed studies will address this unmet need by determining how mild exercise therapy and intra-articular corticosteroid treatments (IA-CST) function independently and in combination to alter molecular and structural conditions of the intra-articular "host environment" that reduce pain and improve the efficacy of cell-based PTOA therapies. The rationale for this project is that identifying non-surgical interventions that increase the efficacy and pain relief of disease modifying OA therapies will greatly improve their cost-effectiveness and the path toward clinical implementation. We hypothesize that mild exercise therapy will improve the efficacy of intra-articular OA therapies by reducing joint inflammation, reversing the pro-catabolic effects of IA-CST, and rescuing epigenetic changes that negatively impact autologous and allogenic stem cell therapies. A key aspect of our approach to testing this hypothesis is to use older (6-12 months old) high-fat diet-induced obese mice. These mice share many clinical features with the Veteran population most in need of OA therapies who are older, obese, and afflicted with metabolic syndrome- related comorbidities. This project capitalizes on our expertise in the use of this pre-clinical animal model to study OA pathophysiology. We will use the destabilized medial meniscus model of PTOA in these mice to complete three specific aims. For each aim, we will determine the independent and combined effects of intra- articular CST (triamcinolone acetonide) and mild treadmill exercise on Aim 1) Joint structural changes, inflammation, and pain-related PTOA functional outcomes, Aim 2) Changes in joint tissue epitranscriptome (RNAseq, DNA methylation) and autologous stem cell chondrogenic potential, and Aim 3) Joint structural and functional outcomes following intra-articular adipose derived stem cell (ADSC) therapy. Successful completion of these aims will: 1) determine the effectiveness of mild exercise to counter the pro-catabolic effects of IA-CST and extend improvements in pain and function, 2) identify genetic mechanisms for how exercise and IA-CST modulate stem cell chondrogenic potential, and 3) determine how exercise and IA-CST modify short-term pain and structural outcomes using an intra-articular stem cell-based PTOA therapy. This knowledge is expected to advance the efficacy of future PTOA therapies by optimizing the joint environment to support stem cell and tissue-engineering-based regenerative medicine strategies.