Traumatic brain injury enhances fracture healing by upregulating VNN1 to activate the Wnt/β-catenin signaling pathway

BACKGROUND: Delayed fracture healing is a significant clinical challenge. Patients with concurrent traumatic brain injury (TBI) exhibit accelerated fracture healing; however, the underlying mechanisms remain poorly understood. This study aimed to identify key genes and molecular pathways that mediate enhanced fracture healing in patients with TBI. METHODS: Transcriptome sequencing was performed to identify differentially expressed genes in the peripheral blood of patients with simple fractures and those with fractures accompanied by TBI. Quantitative real-time PCR (qRT-PCR), western blotting analysis, micro-computed tomography (micro-CT) scanning, and histological examinations were performed on a rat model of fracture with concomitant TBI. The role of vanin-1(VNN1) in fracture healing was assessed together with its relationship with the Wnt/β-catenin signaling pathway. RESULTS: Transcriptomic analysis revealed that VNN1 was significantly upregulated in patients with combined fracture and TBI. In animal models, VNN1 expression peaked early after injury and remained elevated over time. VNN1 knockdown markedly inhibited TBI-induced accelerated fracture healing, reduced callus maturity, and downregulated the expression of osteogenesis-related proteins (Runx2, OCN, OPN, COL1A1). Mechanistically, VNN1 activated the Wnt/β-catenin signaling via a non-canonical pathway, manifested by upregulation of β-catenin, Wnt1, and their downstream target genes, along with increased GSK3β phosphorylation. Inhibition of this pathway reversed the TBI-induced healing effect. CONCLUSIONS: VNN1 is a key factor mediating TBI-induced fracture healing by non-canonically regulating the Wnt/β-catenin signaling pathway to promote osteogenic differentiation and bone tissue maturation. This study provides a novel mechanism for understanding the effects of systemic trauma on local bone repair and offers potential molecular targets for fracture treatment.