Talin1 loss activates DRG neurons to accelerate bone remodeling and fracture healing in mice
Abstract
Background: 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.
Materials and methods: 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.
Results: 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…
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