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

骨关节炎（OA）在美国军人和退伍军人中非常普遍，这是由于关节炎的影响。 创伤和过度使用损伤。其社会经济影响巨大，估计每年接近600亿美元， 并且不存在改善疾病的治疗方法。合作计划的总体目标是制定一个 治疗创伤后骨关节炎（PTOA），将缓解疼痛和改善功能。我们假设 PTOA是由适应不良的修复反应引起的，包括炎症反应的促炎途径的激活。 先天性免疫力反过来导致疼痛、功能丧失和结构衰退。该计划旨在解决 假设通过两个高度整合的目标：（1）开发创新的非药物和关节内 抑制局部疼痛和炎症的疗法，以及（2）优化基于间充质干细胞（MSC）的 修复受损关节的治疗方法。项目5的目标是确定务实的循证 减少PTOA疼痛并增加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进展的治疗方法。 很可能需要联合治疗方法来克服这一障碍，并开发安全和有效的治疗方法。 为退伍军人提供有效治疗。我们建议的研究将通过确定如何温和地解决这一未满足的需求 运动疗法和关节内皮质类固醇治疗（IA-CST）独立发挥作用， 组合以改变关节内"宿主环境"的分子和结构条件， 疼痛和改善基于细胞的PTOA疗法的功效。该项目的基本原理是， 非手术干预，增加疗效和缓解疼痛的疾病修改OA治疗将 大大提高了成本效益和临床实施的途径。我们假设轻微的 运动疗法将通过减少关节炎症来改善关节内OA疗法的功效， 逆转IA-CST的促分解代谢作用，并挽救对免疫系统产生负面影响的表观遗传变化， 自体和同种异体干细胞疗法。我们检验这一假设的方法的一个关键方面是使用 老年（6 - 12月龄）高脂肪饮食诱导的肥胖小鼠。这些小鼠与这些小鼠有许多共同的临床特征。 最需要OA治疗的老年、肥胖和患有代谢综合征的退伍军人人群- 相关合并症。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， 研究OA病理生理学。我们将在这些小鼠中使用不稳定的PTOA内侧半月板模型， 完成三个具体目标。对于每一个目标，我们将确定内部的独立和综合影响， 关节CST（曲安奈德）和轻度踏车运动对目标1）关节结构的变化， 炎症和疼痛相关的PTOA功能结局，目的2）关节组织epitranscriptome的变化 （RNAseq，DNA甲基化）和自体干细胞软骨形成潜力，以及目的3）关节结构和 关节内脂肪干细胞（ADSC）治疗后的功能结果。成功完成 这些目标将：1）确定轻度运动对抗IA-CST促分解作用的有效性 并扩大疼痛和功能的改善，2）确定运动和IA-CST的遗传机制 调节干细胞软骨形成潜力，3）确定运动和IA-CST如何改变短期疼痛 和结构结果使用关节内干细胞为基础的PTOA治疗。这些知识预计将 通过优化支持干细胞的关节环境，提高未来PTOA治疗的疗效， 基于组织工程的再生医学策略。

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.