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

氧化爆发过程中活性氧（ROS）的产生对微生物和被吞噬物质的有效破坏至关重要。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，氧化爆发对炎症的调节和自身免疫的预防至关重要。因此，中性粒细胞胞质因子1 （nadph氧化酶复合体（NOX） 2的一个亚基）突变导致ros生成减少，导致关节炎和多发性硬化症动物模型疾病加重。相比之下，关于氧化破裂对骨稳态影响的信息迄今为止是难以捉摸的。在皮下注射尿酸钠晶体（MSU）引起的局部炎症模型的初步实验中，一只ncf1突变的小鼠表现出强烈的炎症加剧和慢性化以及剧烈的骨转换：而在注射的同侧部位，骨溶解为主，对侧形成大骨疣。该项目的目的是，表征这种ros缺陷骨表型，并将所获得的知识转化为痛风和慢性肉芽肿病（CGD）患者，这是一种由缺陷性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（NETs）和选定的促炎细胞因子形成的作用。如果成功，整个项目获得的发现对于开发治疗慢性炎症、痛风和CGD患者骨破坏的新方法很重要。

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.