Neuro-immune-bone axis in post-traumatic bone regeneration: temporal regulation, dysregulation mechanisms, and...

Post-traumatic bone regeneration extends beyond a mere osteogenic event to encompass a dynamic reparative cascade characterized by the coordinated interplay of inflammation, nerve reinnervation, angiogenesis, mesenchymal stem cell differentiation, and osteoblast-osteoclast coupling. While immune and neural regulations have been independently implicated in bone repair, a unified mechanistic framework and sufficient human evidence regarding the spatiotemporal synergy of neural signals with immune cells-and the extent to which this interaction dictates healing outcomes-remain elusive. Current research suggests that sensory nerves, sympathetic nerves, and their released neuropeptides and neurotransmitters can engage in bidirectional communication with immune cells such as macrophages, T cells, and neutrophils, providing a new conceptual framework for integrating injury perception, inflammatory transition, neurovascular reconstruction, and bone remodeling from the perspective of the "neuro-immune-bone axis". This review examines the temporal dynamics of the immune response and nerve reinnervation during post-traumatic bone repair. It places particular emphasis on the bidirectional interactions between specific neural signals and immune cells, exploring how downstream signaling nodes transduce neural inputs into altered immune states that subsequently influence BMSCs, osteoblasts, angiogenesis, and bone remodeling. Additionally, this article reviews the potential links between abnormal neuro-immune interactions and delayed healing, nonunion, and chronic pain, and discusses the possible alterations of this regulatory network under conditions such as diabetes, osteoporosis, and aging, along with their therapeutic implications. Notably, the evidentiary strength in this field varies considerably: many mechanistic insights are derived from animal models, in vitro studies, or non-fracture tissue injury models, and the effects of certain neuropeptides, sympathetic signals, and immune subsets exhibit significant stage, dose, and tissue-context dependence. Regarding the causal contribution of the neuro-immune axis to human fracture healing and whether targeted interventions can improve clinical bone healing outcomes, long-term longitudinal studies and high-quality clinical validation remain lacking. Therefore, at this stage, it is more appropriate to regard the neuro-immune-bone axis as an integrative working framework for explaining multi-system synergistic repair after trauma, rather than a fully established linear causal pathway. Future research should combine temporal, multicellular, and spatial evidence to identify key regulatory nodes at different repair stages and evaluate their feasibility as stage-specific therapeutic targets.