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: 10376737
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376737
• 关键词: Address; Adipose tissue; Adrenal Cortex Hormones; Allogenic; Analgesics; Animal Model; Animals; Arthralgia; Autologous; Behavior; Body Weight decreased; Caring; 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; 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; Trauma; Triamcinolone Acetonide; Veterans; Weight-Bearing state; Work; arthritic pain; base; bisulfite; bone; bone marrow mesenchymal stem cell; cartilage regeneration; cartilage repair; clinical implementation; comorbidity; cost effectiveness; diet-induced obesity; effective therapy; effectiveness evaluation; engineered stem cells; epigenome; epitranscriptome; feeding; functional outcomes; gait examination; improved; improved functioning; 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.

由于联合的影响 创伤和过度使用伤害。它的社会经济影响很大，估计每年接近600亿美元， 并且不存在调整疾病的治疗。协作计划的总体目标是开发 创伤后骨关节炎（PTOA）的治疗，可缓解疼痛并改善功能。我们假设 PTOA是由适应不良的修复反应引起的，包括激活的促炎途径 先天免疫反过来导致疼痛，功能丧失和结构下降。该程序解决 通过两个高度集成的目的假设：（1）开发创新的非药物和关节内的创新 抑制局部疼痛和炎症的疗法，以及（2）优化间充质干细胞（MSC）的疗法 重建受损关节的疗法。项目5的目的是确定务实的基于证据 减轻PTOA疼痛并使用前临床前疗法提高关节内疗法的功效的干预措施 资深特定健康状况的动物模型。该领域进步的主要障碍正在发展 解决慢性PTOA炎症并阻止疾病结构进展的治疗方法。 可能需要采用联合治疗方法来克服这一障碍并发展安全和 对退伍军人的有效治疗。我们提出的研究将通过确定如何轻度来满足这种未满足的需求 运动疗法和关节内皮质类固醇治疗（IA-CST）独立和在 结合改变关节内“宿主环境”的分子和结构条件，以减少 疼痛并提高基于细胞的PTOA疗法的功效。该项目的理由是确定 non-surgical interventions that increase the efficacy and pain relief of disease modifying OA therapies will 大大提高了他们的成本效益和临床实施的途径。我们假设这种温和 运动疗法将通过减少关节炎症，提高关节内OA疗法的功效， 逆转IA-CST的亲电代谢作用，并营救表观遗传变化，从而对 自体和同种异体干细胞疗法。我们检验该假设方法的关键方面是使用 年龄较大（6-12个月大）高脂饮食引起的肥胖小鼠。这些老鼠与 老年人疗法的资深人群年龄较大，肥胖，患有代谢综合征 - 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的专业知识上 研究OA病理生理学。我们将使用这些小鼠中PTOA的不稳定的弯月面模型 完成三个具体目标。对于每个目标，我们将确定内部内部的独立和联合效应 关节CST（曲安西尔酮乙烯胺）和AIM上的轻度跑步机运动1）联合结构变化， 炎症和与疼痛相关的PTOA功能结果，目标2）关节组织表演组的变化 （RNASEQ，DNA甲基化）和自体干细胞软骨势，目标3）关节结构和 关节内脂肪衍生的干细胞（ADSC）治疗后的功能结果。成功完成 这些目的将：1）确定轻度锻炼对抗IA-CST的促代谢作用的有效性 并扩展疼痛和功能的改善，2）确定运动和IA-CST的遗传机制 调节干细胞软骨势，3）确定运动和IA-CST如何修饰短期疼痛 以及使用关节内干细胞的PTOA治疗的结构结果。期望这些知识 通过优化联合环境以支持干细胞和 基于组织工程的再生医学策略。