Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways

Applying cold to a bone injury can aid healing, though its mechanisms are complex. This study investigates how cold therapy impacts bone repair to optimize healing. Cold was applied to a rodent bone model, with the physiological responses analyzed. Vasoconstriction was mediated by an increase in the transient receptor protein channels (TRPs), transient receptor potential ankyrin 1 (TRPA1; <i>p</i> = 0.012), and transient receptor potential melastatin 8 (TRPM8; <i>p</i> < 0.001), within cortical defects, enhancing the sensory response and blood flow regulation. Cold exposure also elevated hypoxia (<i>p</i> < 0.01) and vascular endothelial growth factor expression (VEGF; <i>p</i> < 0.001), promoting angiogenesis, vital for bone regeneration. The increased expression of osteogenic proteins peroxisome proliferator-activated receptor gamma coactivator (PGC-1α; <i>p</i> = 0.039) and RNA-binding motif protein 3 (RBM3; <i>p</i> < 0.008) suggests that the reparative processes have been stimulated. Enhanced osteoblast differentiation and the presence of alkaline phosphatase (ALP) at day 5 (three-fold, <i>p</i> = 0.021) and 10 (two-fold, <i>p</i> < 0.001) were observed, along with increased osteocalcin (OCN) at day 10 (two-fold, <i>p</i> = 0.019), indicating the presence of mature osteoblasts capable of mineralization. These findings highlight cold therapy's multifaceted effects on bone repair, offering insights for therapeutic strategies.