2. Academic Validation
  3. Dysregulated neutrophils contribute to bone loss in renal osteodystrophy by enhancing osteoclastogenesis: Insights from integrated bioinformatics and experimental validation

Dysregulated neutrophils contribute to bone loss in renal osteodystrophy by enhancing osteoclastogenesis: Insights from integrated bioinformatics and experimental validation

  • Int Immunopharmacol. 2026 Jan 1;168(Pt 2):115947. doi: 10.1016/j.intimp.2025.115947.
Tingwei Lu 1,  Zhirui Dong 2,  Lingyong Jiang 3,  Yuan Dai 4
Affiliations

Affiliations

  • 1 Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 210000, China.
  • 2 Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
  • 3 Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 210000, China. Electronic address: [email protected].
  • 4 Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: [email protected].
PMID: 41314047 DOI: 10.1016/j.intimp.2025.115947
Abstract

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.

Keywords

Chronic kidney disease; Neutrophils; Osteoclastogenesis; Osteoimmune microenvironment; Renal osteodystrophy.

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