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

CMA：缓解关节炎疼痛的软骨修复策略 (CaRe AP)：优化关节内骨关节炎治疗的宿主环境

• 批准号: 10618788
• 负责人: TIMOTHY M GRIFFIN
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618788
• 关键词: Address; Adrenal Cortex Hormones; Allogenic; Analgesics; Animal Model; Animals; Arthralgia; Autologous; Behavior; Body Weight decreased; Cartilage; Catabolism; Cells; Chondrogenesis; Chronic; Clinical; Cumulative Trauma Disorders; Custom; DNA Methylation; Data; Degenerative polyarthritis; Disease; Disease Progression; Environment; Epigenetic Process; Evidence based intervention; Exercise; Exercise Therapy; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; General Population; Genetic; Goals; Health; High Fat Diet; Histology; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Injections; Injury; Intervention; Joints; Knowledge; Limb structure; Magnetic Resonance Imaging; Measures; Medial meniscus structure; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; Methods; Modeling; Molecular; Morphology; Mus; Natural Immunity; Obese Mice; Obesity; Oligonucleotides; Operative Surgical Procedures; Oral; Outcome; Pain; Pathway interactions; Pharmaceutical Preparations; Regenerative Medicine; Research; Risk; Saline; Signal Pathway; Synovial Membrane; Testing; Therapeutic; Tissue Engineering; Tissues; Transforming Growth Factor beta; Trauma; Traumatic Arthropathy; Triamcinolone Acetonide; Veterans; Weight-Bearing state; Work; adipose derived stem cell; arthritic pain; bisulfite; bone; bone marrow mesenchymal stem cell; cartilage regeneration; cartilage repair; clinical implementation; comorbidity; cost effectiveness; diet-induced obesity; economic impact; effective therapy; effectiveness evaluation; engineered stem cells; epigenome; epitranscriptome; feeding; functional improvement; functional outcomes; gait examination; improved; innovation; instrument; joint infection; joint inflammation; joint injury; loss of function; microCT; military service; military veteran; mouse model; novel therapeutics; osteoarthritis pain; pain reduction; pain relief; physically handicapped; pre-clinical; prevent; programs; reconstruction; repair strategy; repaired; response; service member; socioeconomics; stem cell therapy; stem cells; subchondral bone; therapy outcome; transcriptome; transcriptome sequencing; treadmill; treatment optimization; whole genome

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.

由于关节的影响，骨关节炎 (OA) 在美国军人和退伍军人中非常普遍。 外伤和过度使用损伤。其社会经济影响巨大，估计每年接近 600 亿美元， 并且不存在缓解疾病的治疗方法。该合作计划的总体目标是开发一个 治疗创伤后骨关节炎 (PTOA)，可缓解疼痛并改善功能。我们假设 PTOA 是由适应不良修复反应引起的，包括促炎途径的激活 先天免疫反过来会导致疼痛、功能丧失和结构衰退。该计划解决了 通过两个高度整合的目标提出假设：（1）开发创新的非药物和关节内治疗 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）的疗法 重建受损关节的疗法。项目 5 的目标是确定实用的、基于证据的 使用临床前的干预措施减少 PTOA 疼痛并提高关节内治疗的功效 退伍军人特定健康状况的动物模型。该领域取得进展的一个主要障碍是开发 解决慢性 PTOA 炎症并阻止疾病结构性进展的治疗方法。 很可能需要联合治疗方法来克服这一障碍并开发安全和 对退伍军人有效的治疗。我们提出的研究将通过确定温和程度来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，从而减少 疼痛并提高基于细胞的 PTOA 疗法的疗效。该项目的基本原理是确定 提高骨关节炎疾病治疗的疗效和缓解疼痛的非手术干预措施将 大大提高了其成本效益和临床实施路径。我们假设温和 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，并挽救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 年龄较大（6-12 个月大）的高脂肪饮食诱导的肥胖小鼠。这些小鼠与小鼠有许多共同的临床特征 最需要 OA 治疗的退伍军人群体是年龄较大、肥胖且患有代谢综合征的人 相关合并症。该项目利用了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 PTOA 不稳定的内侧半月板模型来 完成三个具体目标。对于每个目标，我们将确定内部的独立和综合影响 关节 CST（曲安奈德）和轻度跑步机运动目标 1) 关节结构变化， 炎症和疼痛相关的 PTOA 功能结果，目标 2) 关节组织表观转录组的变化 （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 关节内脂肪干细胞（ADSC）治疗后的功能结果。顺利完成 这些目标将： 1) 确定轻度运动对抗 IA-CST 促分解代谢作用的有效性 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 如何改善短期疼痛 以及使用基于关节内干细胞的 PTOA 疗法的结构结果。这些知识预计将 通过优化关节环境来支持干细胞和促进未来 PTOA 疗法的功效 基于组织工程的再生医学策略。