Separating Systemic Inflammation From Obesity in Load-Induced Osteoarthritis

 描述（由申请人提供）：骨关节炎的经典定义是由关节/软骨上的过度机械负荷引起的非炎症性关节炎。骨关节炎也与肥胖有关，肥胖通常归因于体重引起的关节负荷增加。多种证据表明，除了机械负荷外，骨关节炎的发生还有非机械因素。与肥胖和代谢综合征相关的低度慢性全身性炎症被认为是骨关节炎的非机械性因素。然而，在大多数动物模型和患者中，肥胖和全身炎症的共同发生使得迄今为止难以区分这两种因素对骨关节炎的影响。拟定的探索性/开发性研究项目基于以下假设：起源于肠道的低度慢性全身性炎症会增强机械负荷对骨关节炎发展的不良影响。我们建议使用TLR 5缺陷小鼠将全身性炎症的影响与肥胖分开，TLR 5缺陷小鼠自发地发展肠道植物群生态失调，导致肠道炎症、低度慢性全身性炎症和代谢综合征样表型。使用负荷诱导的骨关节炎模型和TLR 5缺陷小鼠中的炎症起源于肠道而不是肥胖的事实，该项目包括一个目的：确定在三种条件下施加的负荷大小与TLR 5缺陷小鼠中骨关节炎发展之间的关系：轻度炎症/轻度体重增加（自然状态）、轻度炎症/正常体重（限制进食）和正常炎症/正常体重（抗生素治疗）。我们的研究结果将测试这样一种观点，即即使在没有肥胖的情况下，全身性炎症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微生物群（TLR 5 KO表型的上游原因）的变化可以影响骨关节炎的易感性。

 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.