Dysregulated neutrophils contribute to bone loss in renal osteodystrophy by enhancing osteoclastogenesis: Insights...

Renal osteodystrophy (ROD) is a major debilitating skeletal complication of chronic kidney disease characterized by dysregulated bone remodeling. Neutrophils are essential for bone homeostasis. However, their functionality in the ROD osteoimmune microenvironment remains unclear. To investigate the crosstalk between neutrophils and bone metabolic imbalance in ROD, we firstly performed transcriptomic profiling in patients with ROD, revealing a pronounced disruption of bone homeostasis. These findings were corroborated in a murine model of ROD, which demonstrated an osteoporotic phenotype and increased osteoclast activity. Through integrated bioinformatics and experimental validation, we identified substantial functional impairments of neutrophils in the ROD bone microenvironment, including downregulated degranulation, reduced neutrophil extracellular trap formation, and decreased abundance. In co-culture systems, ROD-derived neutrophils potently enhanced osteoclastogenesis from bone marrow-derived macrophages indirectly through the modulation of cytokine release, which was mediated by the PI3K-Akt signaling pathway. Furthermore, potential biomarkers and a therapeutic compound were identified and preliminarily validated via in silico and in vitro experiments, highlighting the translational prospects for ROD management. Our findings demonstrated that neutrophil dysfunction disrupts osteoclastogenesis-osteogenesis equilibrium, contributing to pathological bone loss in the ROD bone microenvironment.