Traumatic Brain Injury Effects on Bone Healing

Traumatic brain injury (TBI) exerts a profound influence on the process of bone repair, frequently resulting in accelerated callus formation and enhanced bone volume at fracture sites. This phenomenon is underpinned by a complex interplay between the injured central nervous system, the immune response and skeletal cells. Following TBI, injured neurons release bioactive factors that travel systemically to the bone microenvironment, stimulating osteoprogenitor cells and promoting vascularisation. Concurrently, alterations in sympathetic tone and neuroendocrine signalling reshape the profile of immune cells within the fracture haematoma, favouring anti-inflammatory macrophage subsets and a supportive milieu for bone deposition. Circulating extracellular vesicles and enriched microRNAs further modulate osteoblastic differentiation, while shifts in haematopoietic stem cell commitment augment the pool of regenerative myeloid cells. These central-to-peripheral signals converge to accelerate endochondral ossification, enlarge the fracture callus and improve biomechanical properties of the healed bone. Understanding these brain-bone crosstalk mechanisms holds promise for novel therapeutic strategies to enhance fracture repair in patients without TBI and to mitigate adverse skeletal effects in those with severe head injury.

Research from Nature Portfolio

One study uncovered that following TBI, neurons—particularly in the hippocampus—release microRNA-enriched small extracellular vesicles (sEVs) that home to osteoprogenitor cells in bone. Two specific microRNAs within these vesicles promote osteogenesis by targeting negative regulators of bone formation, and surface fibronectin enhances sEV targeting to fracture sites, offering a potential route for bone-targeted delivery of therapeutic vesicles. Another investigation employed a controlled murine polytrauma model combining closed head injury with tibial fracture to dissect neurological from humoral effects. When the fracture occurred contralaterally to the brain injury, there was a significant increase in callus size and early bone formation, linked to a distinct neuroinflammatory response. These findings establish clear evidence of central regulation of fracture healing through both extracellular vesicle-mediated communication and crossed neuroanatomical pathways.

Traumatic Brain Injury Effects on Bone Healing publication trend

The graph below shows the total number of articles in traumatic brain injury effects on bone healing across all publications each year (not limited to Nature Index journals).

Technical terms

Small extracellular vesicles (sEVs): membrane-bound particles secreted by cells that carry proteins, lipids and nucleic acids to mediate intercellular communication.

Osteoprogenitors: precursor cells in bone marrow capable of differentiating into osteoblasts and forming new bone.

Callus: the temporary, unmineralised tissue formed at a fracture site that precedes woven and lamellar bone.

Adrenergic signalling: cellular communication through adrenaline or noradrenaline binding to adrenergic receptors, affecting immune and skeletal cells.

Macrophage polarization: the process by which macrophages adopt pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes.

Haematopoietic stem cells (HSCs): multipotent stem cells in bone marrow that give rise to all blood-lineage cells.

MicroRNA (miRNA): short non-coding RNAs that regulate gene expression post-transcriptionally, influencing cell differentiation and function.

References

1. Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors. Nature Communications (2021).
2. Differential fracture response to traumatic brain injury suggests dominance of neuroinflammatory response in polytrauma. Scientific Reports (2019).
3. Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing. Signal Transduction and Targeted Therapy (2023).
4. Circulating MiRNA-21-enriched extracellular vesicles promote bone remodeling in traumatic brain injury patients. Experimental & Molecular Medicine (2023).
5. Altered early immune response after fracture and traumatic brain injury. Frontiers in Immunology (2023).