The bidirectional role of neutrophils in the regulation of bone metabolism: a review of research progress and mechanism

Abstract

Bone homeostasis is maintained through a dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. With the rapid development of osteoimmunology, increasing attention has been directed toward the role of immune cells in the regulation of bone metabolism. Neutrophils, as the most abundant innate immune cells in the bone marrow, are now recognized not only as key effectors of inflammation but also as important regulators of bone microenvironment homeostasis and bone remodeling. This review summarizes current advances in the understanding of neutrophil-mediated regulation of bone metabolism, focusing on their dual roles in osteogenesis and osteoclastogenesis. During the early stages of bone repair, neutrophils may facilitate bone regeneration by clearing necrotic debris, promoting angiogenesis, and modulating mesenchymal stem cells (MSCs) function. However, in pathological settings such as persistent inflammation, metabolic dysfunction, and aging, neutrophil dysregulation can suppress osteogenesis and enhance osteoclastogenesis through the release of inflammatory mediators, reactive oxygen species, and neutrophil extracellular traps (NETs), ultimately contributing to bone metabolic imbalance. Notably, NETs exhibit context-dependent effects in bone remodeling and may either support repair or aggravate bone destruction under different pathological conditions. Overall, neutrophils function as critical intermediates linking immune responses with bone remodeling. Their diverse effects on bone metabolism are largely determined by their activation status and the surrounding microenvironment. Elucidating the mechanisms underlying neutrophil-mediated regulation of bone metabolism may offer new insights and potential therapeutic targets for osteoporosis, inflammatory bone destruction, and impaired bone healing.