Neutrophils: The Overlooked Regenerative Role in Bone Repair.

Bone repair is a complex regenerative process involving inflammatory responses, vascular remodeling, and stem cell-mediated osteogenesis, wherein the immune microenvironment plays a critical regulatory role. Neutrophils have long been recognized as short-lived, pro-inflammatory effector cells primarily responsible for pathogen clearance and tissue debridement, and may even trigger inflammatory tissue damage when abnormally activated. Their regenerative potential in bone healing has, therefore, been significantly underestimated. Emerging evidence suggests that neutrophils are pivotal contributors to the bone repair process, exhibiting remarkable functional diversity that extends beyond their classical inflammatory roles. During the repair process, neutrophils assist in extracellular matrix (ECM) deposition and secrete pro-angiogenic factors, thereby fostering the early repair microenvironment. Meanwhile, they modulate the immune microenvironment through bidirectional interactions with macrophages and other immune cells, and promote bone regeneration by facilitating the recruitment and osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs). Recent studies have also begun to elucidate the temporal dynamics and circadian regulation of neutrophil functions during tissue repair. Conversely, under pathological conditions, aberrantly activated neutrophils can disrupt these finely tuned processes and drive pathological bone repair. Collectively, these findings necessitate a redefinition of the role of neutrophils in bone repair and underscore the importance of exploring new concepts and directions in neutrophil biology.