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

• 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
• 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

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）是一种常见的退行性过程，是美国人口的主要健康问题。 虽然已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的发病机制，只有部分阐明。传统的想法是肌肉 活动通过调节关节负荷和改变骨强度直接影响关节的生物力学， 减轻OA严重程度。然而，肌肉也会分泌具有旁分泌效应的因子。有多少信息 影响关节的因素以及它们如何随着运动和肌肉病理而变化尚不清楚。 利用细胞培养研究，我们发现，在培养中锻炼的人类肌肉细胞产生分泌因子， 改变人关节外植体中OA严重程度的重要基因的表达。然后我们修改了一个 这种方法允许两只小鼠之间使用导管进行循环交换，而不是标准的共生 法这种方法允许在一只动物中研究循环因子对OA严重程度的作用 在另一种动物中，而动物具有不同的运动活动水平。我们的初步数据显示 当久坐动物的循环系统与非久坐动物共享时， 锻炼的动物在这里，我们将开发方法来识别这些因素，并将表征体内 策略，以测试这些因素在啮齿动物的功能。我们将致力于实现以下目标： 基于我们的数据显示，来自运动肌肉的条件培养基产生抑制 在骨关节炎软骨外植体中OA严重程度的重要基因表达，我们将进一步评估这些 不同运动方式和肌细胞年龄的旁分泌效应。为了鉴别差异分泌的 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来交换循环血液，使动物能够共享 循环，同时进行不同的体力活动方案，我们将确定如何持续时间 运动、血液交换程序的次数以及血浆或细胞组分改变OA表型 与外科关节损伤有关运动调节的最差异蛋白质的表达 将使用ELISA在来自运动小鼠和静止小鼠的血清之间比较在第一个目的中鉴定的抗体。 已鉴定的蛋白质可以作为靶点，因此，我们的数据可以确定一种治疗方法， 这种方法可以用来减轻OA的严重程度。此外，这项工作将确定具体的 运动对OA严重程度的生化影响。