Separating Systemic Inflammation From Obesity in Load-Induced Osteoarthritis

区分负荷引起的骨关节炎中的全身炎症和肥胖

• 批准号: 8885177
• 负责人: Christopher John Hernandez
• 金额: $ 20.33万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885177
• 关键词: Adipocytes; Adverse effects; Animal Model; Antibiotics; Arthritis; Attention; Body Weight; Cartilage; Chronic; Degenerative polyarthritis; Development; Diet; Disease; Fatty acid glycerol esters; Flagellin; Human; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin Resistance; Interleukin-12; Intervention; Joints; Lead; Link; Mechanics; Metabolic syndrome; Methods; Mild obesity; Modeling; Mus; Obesity; Oral; Pain; Pathology; Patients; Phenotype; Predisposition; Process; Production; Regulation; Research Project Grants; Stimulus; Synovitis; TLR5 gene; Testing; Toll-Like Receptor 5; Weight Gain; Work; arthropathies; base; bone; cytokine; feeding; gut microbiota; human subject; joint loading; microbiome; novel; prevent; public health relevance; receptor; research study; Adipocytes; Adverse effects; Animal Model; Antibiotics; Arthritis; Attention; Body Weight; Cartilage; Chronic; Degenerative polyarthritis; Development; Diet; Disease; Fatty acid glycerol esters; Flagellin; Human; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin Resistance; Interleukin-12; Intervention; Joints; Lead; Link; Mechanics; Metabolic syndrome; Methods; Mild obesity; Modeling; Mus; Obesity; Oral; Pain; Pathology; Patients; Phenotype; Predisposition; Process; Production; Regulation; Research Project Grants; Stimulus; Synovitis; TLR5 gene; Testing; Toll-Like Receptor 5; Weight Gain; Work; arthropathies; base; bone; cytokine; feeding; gut microbiota; human subject; joint loading; microbiome; novel; prevent; public health relevance; receptor; research study

 DESCRIPTION (provided by applicant): Osteoarthritis is classically defined as a non-inflammatory arthritis caused by excessive mechanical loading on the joint/cartilage. Osteoarthritis is also linked to obesity, which is commonly attributed to increased joint load caused by body weight. Multiple lines of evidence suggest that, in addition to mechanical loading, there are non-mechanical contributors to the development of osteoarthritis. Low-grade chronic systemic inflammation, associated with obesity and the metabolic syndrome, has been implicated as a non-mechanical contributor to osteoarthritis. However, the co-occurrence of obesity and systemic inflammation in most animal models and patients has so far made it difficult to separate the effects of the two factors on osteoarthritis. The proposed Exploratory/Developmental Research project is based on the hypothesis that low-grade chronic systemic inflammation originating in the gut enhances the adverse effects of mechanical load on the development of osteoarthritis. We propose separating the effects of systemic inflammation from obesity using the TLR5 deficient mouse, which spontaneously develops gut flora dysbiosis leading to gut inflammation, low-grade chronic systemic inflammation and a metabolic syndrome-like phenotype. Using a load-induced osteoarthritis model and the fact that inflammation in the TLR5 deficient mouse originates in the gut rather than from obesity, the project includes one aim: to determine the relationship between applied load magnitude and development of osteoarthritis in the TLR5 deficient mouse under three conditions: mild inflammation/mild increased body weight (natural state), mild inflammation/normal body weight (limit fed), and normal inflammation/normal body weight (antibiotic treated). Our findings will tes the idea that systemic inflammation influences susceptibility to osteoarthritis even in the absence of obesity and has the potential to provide the first evidence that changes in gut microbiota (the upstream cause of the TLR5KO phenotype) can influence susceptibility to osteoarthritis.

 描述（由适用提供）：骨关节炎经典定义为关节/软骨上过多的机械负荷引起的非炎性关节炎。骨关节炎也与肥胖有关，这通常归因于体重引起的关节负荷增加。多种证据表明，除了机械载荷外，还有非机械性促进骨关节炎的贡献者。与肥胖症和代谢综合征有关的低级慢性全身性炎症已被实施为骨关节炎的非机械贡献者。然而，到目前为止，大多数动物模型和患者的肥胖和全身炎症的同时存在使这两个因素对骨关节炎的影响很难分开。拟议的探索性/发育研究项目基于以下假设：低级慢性全身性炎症起源于肠道，从而增强了机械负荷对骨关节炎发展的不利影响。我们建议使用TLR5缺乏小鼠将全身感染与肥胖的作用分开，该小鼠在赞助的情况下发展了肠道菌群营养不良，导致肠道注射，低度慢性全身感染和代谢综合征样表型。 Using a load-induced osteoarthritis model and the fact that inflammation in the TLR5 deficiency mouse originates in the gut rather than from observation, the project includes one aim: to determine the relationship between applied load magnitude and development of osteoarthritis in the TLR5 deficient mouse under three conditions: mild infection/mild increased body weight (natural state), mild infection/normal body weight (limit fed), and normal infection/normal body weight （抗生素治疗）。我们的发现将表明，即使没有肥胖症，系统感染也会影响骨关节炎的易感性，并有可能提供第一个证据，表明肠道菌群的变化（TLR5KO表型的上游原因）可能会影响对骨关节炎的易感性。