Abstract
<title>Abstract</title> <p>Compound injuries (fractures of extremities with traumatic brain injury. TBI), are commonly complicated by pathological callus overgrowth and aberrant fracture healing with unclear mechanisms. We previously identified a periaxonal space (PAS) of peripheral nerves which mediate (through cerebrospinal fluid, CSF flow) metabolic communications between central nervous system and peripheral organs. Here we demonstrate that CSF flow through PAS contributes to the pathogenesis of aberrant callus. After eliminating interferences from circulation and fractures, the metabolomics revealed three TBI-specific metabolites delivered to fractured bone through PAS. These include L-methionine (derived from neurons), 16:0/18:2-phosphatidylcholine (PLPC) and 18:0/18:2-phosphatidylcholine (SLPC), both derived from astrocytes,. L-methionine promotes proliferation of chondrocytes and apoptosis of osteoclasts, whereas PLPC and SLPC jointly facilitate osteoblast and chondrocyte proliferation; all three substances synergistically drive emergence of pathological callus. Blocking ependymocyte-regulated CSF flow through PAS rescues aberrant bone repair in compound trauma. Our study establishes the PAS-mediated neurometabolic regulatory axis, elucidates the core metabolic mechanism of TBI-associated aberrant fracture healing, and identifies potential metabolic targets for clinical intervention to facilitate healing of complex fractures accompanied by CNS injury.</p>