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Nevertheless, the precise pathomechanisms by which obesity impairs fracture healing remain insufficiently understood. Multiple studies have identified neutrophil granulocytes as key players in the systemic immune response, being the predominant immune cells in early fracture hematomas. This study identified a previously unreported critical period for neutrophil infiltration into the callus. In\u00a0vivo experiments demonstrated that diet\u2010induced obesity (DIO) mice showed earlier neutrophil infiltration, along with increased formation of neutrophil extracellular traps (NETs), compared to control mice during the endochondral phase of fracture repair. Furthermore, Padi4 knockout was found to reduce NET formation and mitigate the fracture healing delays caused by high\u2010fat diets. Mechanistically, in\u00a0vitro analyses revealed that NETs, by activating NLRP3 inflammasomes, inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and concurrently promoted M1\u2010like macrophage polarization. These findings establish a connection between NET formation during the endochondral phase and delayed fracture healing, suggesting that targeting NETs could serve as a promising therapeutic approach for addressing obesity\u2010induced delays in fracture recovery.<\/jats:p>","DOI":"10.1096\/fj.202401523r","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T10:35:24Z","timestamp":1729766124000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Increased neutrophil extracellular traps caused by diet\u2010induced obesity delay fracture healing"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3490-9142","authenticated-orcid":false,"given":"Xuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Xuanwu Hospital Capital Medical University  Beijing China"},{"name":"National Clinical Research Center for Geriatric 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