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

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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.