Talin1 loss activates DRG neurons to accelerate bone remodeling and fracture healing in mice

Bone tissue is densely innervated by sensory nerve fibers, whose roles in bone remodeling and regeneration are poorly defined. This study aims to investigate the physiological function of Talin1, a key focal adhesion protein, in dorsal root ganglion (DRG) neurons in pain processing and its specific impact on bone remodeling and fracture healing. We utilized a transgenic mouse model ( Advillin-Cre ERT2 ; Talin1 fl/fl ) to delete Talin1 expression in sensory neurons under tamoxifen induction. Pain sensitivity, bone mass, and fracture healing were evaluated in adult mice. Transcriptomic analysis, immunofluorescence, western blot, scanning and transmission electron microscopy, alongside a highly localized pharmacological inhibition model using BIBN-loaded hydrogels, were employed to delineate the underlying mechanisms. Talin1 is predominantly expressed in C-fiber DRG neurons and its expression is significantly downregulated following bone fracture. Talin1 loss markedly activates DRG sensory neurons and increases mechanical, but not thermal, pain sensitivity in mice. Concurrently, Talin1 deficiency inhibits mitophagy and impairs mitochondrial function, as indicated by altered mitochondrial morphology, abnormal reactive oxygen species production and reduced mitochondrial membrane potential. Furthermore, beyond its role in nociception, Talin1 loss not only increases bone mass in both adult and aged mice but also accelerates fracture healing by modulating bone remodeling. This pro-healing phenotype coincides with increased expression of calcitonin gene-related peptide (CGRP) in DRG neurons. Critically, pharmacological inhibition of CGRP receptors at the fracture site by BIBN abolishes the fracture healing-promoting effect caused by Talin1 loss. Our studies demonstrate that Talin1 plays a pivotal role in modulating sensory neuron activation, pain perception, and bone remodeling. Specifically, Talin1 loss accelerates bone repair by upregulating CGRP, thereby establishing a Talin1-CGRP signaling axis that mediates sensory neuron control of fracture healing. This research highlights the dual role of Talin1 in sensory neurons in modulating both pain perception and bone remodeling, and emphasizes the potential for targeting Talin1 signaling as a therapeutic strategy to alleviate pain or to accelerate fracture healing.