The impact of neutrophil extracellular traps on bone remodeling and regeneration in health and disease

骨骼和免疫细胞之间的相互作用是维持骨骼完整性和控制损伤后再生的核心。骨重建和再生受损是成骨细胞和骨吸收破骨细胞活性失衡引起的高度相关的疾病，常与中性粒细胞功能障碍有关。在这里，我们的初步数据表明，中性粒细胞外陷阱(NETS)，一种进化上保守的防御机制，旨在杀死细菌，深刻影响骨生物学。我们假设，中性粒细胞感知微观和宏观的骨损伤，并通过Nets释放(NETsis)协调骨细胞的分化和功能。该项目将定义骨源性因子是如何诱导NETsis的，以及Nets的成分如何影响骨形成和吸收。骨骼重塑和再生的生理和病理生理学模型将在Net形成或分辨率受损的小鼠中进行研究。在体外和体内对Share Nets组分的蛋白质组学将与特定的检测系统相结合，以确定关键的骨骼介体并进一步测试它们的功能。总体而言，该项目将探索具有高度临床相关性的先天性免疫系统和骨生物学之间的一种新的串扰。

The interplay between bone and immune cells is central to maintaining bone integrity and governing regeneration after injury. Impaired bone remodeling and regeneration are highly relevant disorders caused by imbalanced activities of bone-forming osteoblasts and bone-resorbing osteoclasts, which are often associated with neutrophil dysfunction. Here, our preliminary data suggest that 'neutrophil extracellular traps' (NETs), an evolutionarily conserved defense mechanism designed to kill bacteria, profoundly affect bone biology. We hypothesize that neutrophils sense microscopic and macroscopic bone injury and orchestrate bone cell differentiation and function through NETs release (NETosis). The project will define how NETosis is induced by bone-derived factors and how NETs components affect bone formation and resorption. Physiological and pathophysiological models of bone remodeling and regeneration will be studied in mice with impaired NETs formation or resolution. Proteomics of shed NETs components in vitro and in vivo will be combined with specific assay systems to identify key skeletal mediators and further test their function. Overall, this project will explore a novel crosstalk between the innate immune system and bone biology with high clinical relevance.