NSAIDs impair fracture healing by disrupting neutrophil-mediated repair
Zappia, J.; McGowan, L. M.; Chatwin, R. M.; Sevil, R.; Fernandes, B. H.; Gillard, B. T.; Moss, J. J.; Jones, C. P.; cross, s.; Das, N. R.; Kemp, J. P.; Amulic, B.; Hammond, C. L.
Show abstract
Neutrophils are among the first immune cells recruited to fractures, yet their contribution to bone repair remains poorly understood. Using live imaging and neutrophil perturbation in adult zebrafish, we show that neutrophils establish the early fracture microenvironment. Neutrophils rapidly accumulated at fractures, underwent NETosis, and exhibited transcriptional programmes associated with matrix remodelling. Compromising neutrophil recruitment, via ibuprofen treatment or orthogonal perturbations, increased fracture non-union, delayed osteoblast differentiation, impaired mineralisation, and altered callus architecture. Mechanistically, neutrophils actively interacted with extracellular matrix proteins, including laminin, fibronectin, and collagen I, through uptake, trafficking and secretion-associated pathways. Together, our findings reveal that neutrophils establish a provisional emergency fracture matrix that templates subsequent bone repair, providing a mechanistic link between early non-steroidal anti-inflammatory drug (NSAID) exposure and impaired skeletal regeneration.
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