Exercise Induced Muscle Secreted Factors That Modify Osteoarthritis (OA) Severity

运动诱发的肌肉分泌因子可改变骨关节炎 (OA) 的严重程度

基本信息

批准号：
10302972
负责人：
Benjamin Aaron Alman
金额：
$ 17.71万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302972
关键词：
Address Affect Age Aging Animal Model Animals Antibodies Attenuated Biochemical Biomechanics Blood Blood Circulation Cartilage Catheters Cell Culture Techniques Cell Fraction Characteristics Coculture Techniques Data Degenerative polyarthritis Down-Regulation Electric Stimulation Enzyme-Linked Immunosorbent Assay Exercise Exposure to Fracture Future Gene Expression Genes Genetic Genetic Predisposition to Disease Health Histologic Human Human Engineering In Vitro Joints Mass Spectrum Analysis Meniscus structure of joint Morbidity - disease rate Mus Muscle Muscle Cells Operative Surgical Procedures Pain Parabiosis Pathogenesis Pathology Pharmacology Phenotype Physical activity Plasma Population Procedures Process Proteins Recombinant Proteins Regimen Research Personnel Rodent Role Serum Serum Proteins Severities Skeletal Muscle Symptoms Techniques Tendon structure Testing Therapeutic Time Tissue Engineering Tissues Work base bone bone strength disability in vivo joint injury joint loading ligament injury mimetics mouse model muscle strength neutralizing antibody novel paracrine protein function repaired sarcopenia sedentary targeted treatment

项目摘要

Osteoarthritis (OA) is a common degenerative process that is a major health problem in the US population. While it is known that muscle strength and exercise can modulate OA symptoms, the mechanism by which skeletal muscle alters OA pathogenesis is only partly elucidated. The conventional thought is that muscle activity directly affects the joint biomechanically by modulating joint loading and altering bone strength, attenuating OA severity. However, muscle also secretes factors that can have paracrine effects. How such factors affect the joint and how they change with exercise and in muscle pathologies is not known. Using cell culture studies, we found that human muscle cells exercised in culture produce secreted factors that alter the expression of important genes in OA severity in human articular explants. We then modified an approach that allows circulatory exchange between two mice using catheters rather than a standard parabiosis technique. This approach allows the study of the role of circulating factors in one animal on the severity of OA in another animal, while the animals have different exercise activity levels. Our preliminary data shows the downregulation of genes important in OA severity in a sedentary animal when its circulation is shared with an exercised animal. Here we will develop approaches to identify these factors and will characterize an in-vivo strategy to test the function of such factors in rodents. We will undertake the following aims: Building on our data showing that conditioned media from exercised muscle produces factors that inhibit expression of genes important in OA severity in osteoarthritic cartilage explants, we will further evaluate these paracrine effects for different exercise regimes and ages of the muscle cells. To identify differentially secreted proteins, we will use mass spectroscopy secretome analysis. Using our modified catheters based approach to exchange circulating blood, allowing animals to share a circulation while undertaking different physical activity regimens, we will determine how the duration of exercise, number of blood exchange procedures, and plasma or cell fractions alter the OA phenotype associated with a surgical joint injury. Expression of the most differentially regulated proteins by exercise identified in the first aim will be compared between the serum from exercised and quiescent mice using ELISA. Identified proteins could be targeted pharmacologically and as such, our data may identify a therapeutic approach that could be used to attenuate the severity of OA. Furthermore, this work will define the specific contribution of biochemical effects of exercise on OA severity.

骨关节炎（OA）是一个常见的退化过程，是美国人口中的主要健康问题。虽然众所周知，肌肉力量和运动可以调节OA症状，但其机制骨骼肌改变OA发病机理仅部分阐明。传统的想法是肌肉活动通过调节关节载荷和改变骨强度直接影响关节的生物力学，减轻OA的严重性。但是，肌肉还分泌可能具有旁分泌作用的因素。如何这样因素影响关节及其随着运动和肌肉病理而变化的因素尚不清楚。使用细胞培养研究，我们发现在培养中行使的人类肌肉细胞会产生分泌的因素改变了人类关节外植体中重要基因在OA严重程度中的表达。然后我们修改了方法可以使用导管在两只小鼠之间进行循环交换，而不是标准抛物线技术。这种方法允许研究一只动物在OA严重程度中循环因子的作用在另一只动物中，动物的运动活动水平不同。我们的初步数据显示当基因在久坐动物的循环中与A的循环中的OA严重程度下调运动动物。在这里，我们将开发方法来识别这些因素，并将表征一个体内测试啮齿动物中此类因素功能的策略。我们将实现以下目标：基于我们的数据，表明肌肉运动的条件媒体会产生抑制的因素在骨关节炎软骨外植体中重要的OA严重程度的基因表达，我们将进一步评估这些旁分泌效应对肌肉细胞的不同运动状态和年龄。识别差分分泌的蛋白质，我们将使用质谱分泌组分析。使用我们改良的基于导管的方法交换循环血液，使动物共享在进行不同的体育活动方案时，我们将确定持续时间运动，血液交换程序的数量以及血浆或细胞分数改变OA表型与手术关节损伤有关。通过运动表达最差异调节的蛋白质使用ELISA的运动和静态小鼠的血清中，将在第一个目标中识别出。鉴定出的蛋白质可以在药理学上靶向，因此，我们的数据可以识别出治疗性可用于减轻OA严重程度的方法。此外，这项工作将定义特定运动对OA严重程度的生化作用的贡献。