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.

骨关节炎（OA）在美国军人和退伍军人中非常普遍，由于关节的影响