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

骨和免疫细胞之间的相互作用是维持骨完整性和控制损伤后再生的核心。骨重塑和再生受损是由成骨细胞和骨吸收破骨细胞活动失衡引起的高度相关的疾病，通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，深刻地影响骨生物学。我们假设中性粒细胞感知微观和宏观骨损伤，并通过net释放协调骨细胞分化和功能（NETosis）。该项目将定义骨源性因子是如何诱导NETosis的，以及net成分是如何影响骨形成和骨吸收的。将在NETs形成或溶解受损的小鼠中研究骨重塑和再生的生理和病理生理模型。体外和体内shed NETs组分的蛋白质组学将与特定的分析系统相结合，以确定关键的骨骼介质并进一步测试其功能。总体而言，本项目将探索具有高度临床意义的先天免疫系统与骨生物学之间的新型串扰。

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.