The role of the oxidative burst in bone remodeling during chronic inflammation

慢性炎症期间氧化爆发在骨重塑中的作用

• 批准号: 237651806
• 负责人: Professor Dr. Martin Herrmann
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237651806?language=en
• 关键词: role; oxidative; burst; bone; remodeling

The production of reactive oxygen species (ROS) during the oxidative burst is essential for the efficient destruction of microorganisms and phagocytosed material. In the classical view, the oxidative burst has been connected to exacerbation of inflammation and collateral tissue damage. However, a change of paradigm has occurred during the last years: there is evidence that the oxidative burst is of crucial importance for the regulation of inflammation and the prevention of autoimmunity. Thus, diminished ROS-production caused by a mutation in neutrophil cytosolic factor 1 (Ncf1), a subunit of the NADPH-oxidase complex (NOX) 2, causes aggravation of disease in animal models of arthritis and multiple sclerosis. In contrast, information on the influence of the oxidative burst on bone homeostasis is so far elusive. In preliminary experiments in a model of local inflammation induced by subcutaneous injection of monosodium urate crystals (MSU), an Ncf1-mutated mouse exhibited strong exacer-bation and chronification of inflammation and dramatic bone turnover: while on the ipsilateral site of the injection, osteloysis was predominant, large osteophytes were building on the contralateral side. The aim of this project is, to characterize this ROS-deficient bone phenotype and to translate the gained knowledge to patients with gout and chronic granulomatous disease (CGD), a human disease caused by a defective oxidative burst. In particular, we will address the roles of the formation of neutrophil extracellular traps (NETs) and of selected pro-inflammatory cytokines, respectively. If successful, the findings gained throughout this project could be important for the development of new treatment approaches for bone destruction in patients with chronic inflammation, gout, and CGD.

在氧化爆发过程中产生的活性氧种(ROS)对于有效地破坏微生物和吞噬的物质是必不可少的。在经典观点中，氧化爆发与炎症加剧和附带组织损伤有关。然而，在过去的几年里，范式发生了变化：有证据表明，氧化猝发对于调节炎症和预防自身免疫至关重要。因此，在关节炎和多发性硬化症的动物模型中，由NADPH-氧化酶复合体(NOX)2的一个亚单位-中性粒细胞胞浆因子1(NCF1)突变引起的ROS产生减少会导致疾病的恶化。相比之下，关于氧化爆发对骨骼稳态的影响的信息到目前为止还不清楚。在皮下注射尿酸单钠晶体(MSU)所致局部炎症模型的初步实验中，Ncf1基因突变的小鼠表现出强烈的炎症反应和时序化，以及显著的骨转换：而在注射的同侧，骨溶解占主导地位，对侧有大的骨赘形成。这个项目的目的是，描述这种ROS缺乏的骨表型，并将所获得的知识转化为痛风和慢性肉芽肿病(CGD)的患者，CGD是一种由缺陷氧化爆发引起的人类疾病。特别是，我们将分别讨论中性粒细胞胞外陷阱(Net)和选定的促炎细胞因子的形成所起的作用。如果成功，在整个项目中获得的发现可能对开发慢性炎症、痛风和CGD患者骨破坏的新治疗方法具有重要意义。