GFRα2 identified in TBI-induced bone healing is a novel therapeutic target for osteoporosis via osteogenesis and angiogenesis

Background: Osteoporosis (OP) is a systemic disease featured by reduced bone mass, deteriorated microstructure and elevated fracture risk. Traditional therapies mainly target direct regulators of bone remodeling. Emerging evidence suggests a critical crosstalk between the skeletal and nervous systems. Traumatic brain injury (TBI) markedly accelerates fracture healing, which holds great potential for OP treatment, yet the underlying mechanism remains unclear. Methods: A mouse TBI plus femoral fracture model was established. Micro-CT, histomorphometry and transcriptome sequencing were performed. In vitro studies included qPCR, Western blot, ALP/Alizarin Red staining, co-culture, ELISA and tube formation assays. Ovariectomized (OVX) mice received tail vein injection of Gfrα2 overexpression plasmid or siRNA for in vivo validation. Results: TBI significantly accelerated fracture healing with elevated GFRα2 in callus BMSCs. GFRα2 promoted BMSC osteogenesis by maintaining iron homeostasis via Ferritin Heavy Chain 1 (FTH1) and enhanced angiogenesis by increasing VEGFD secretion. In OVX mice, GFRα2 overexpression markedly improved bone mineral density, trabecular microstructure, bone formation rate and intraosseous angiogenesis. Conclusions: GFRα2 serves as a key hub linking TBI to accelerated bone formation via dual effects on osteogenesis and angiogenesis. Targeting GFRα2 represents a promising therapeutic strategy against osteoporosis. The translational potential of this article: This study identifis GFRα2 as a key mediator linking traumatic brain injury-accelerated bone formation to osteogenesis and angiogenesis. Targeting GFRα2 effectively ameliorates bone loss in osteoporotic mice by restoring both bone formation and intraosseous vascularization. These findings establish a novel neuro-osteogenic regulatory axis and provide a promising molecular target for developing new therapeutic strategies to treat osteoporosis and improve fracture healing in clinical practice.