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

Authors

Huibo Ti, Zhenyu Zhang, Huaxin Kang, Yuechun Chen, Keyue Zhang, Shuwen Shi, Xian Wu, Zixin Luo, Xingchen Yao, Xielin Yan, Junjie Wu, Zhengdong Yuan, Hao Nie, Feng-Lai Yuan, Xia Li

Published in

Journal of orthopaedic translation. Volume 59. Pages 101146. Epub Jul 09, 2026.

Abstract

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.
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.
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.
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.
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.

PMID:
42472045
Bibliographic data and abstract were imported from PubMed on 19 Jul 2026.

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