Regeneration of Periodontal Ruffini Endings in NT-4/5 -KO Mice

Objectives: The expression of TrkB, a high affinity neurotrophin receptors, have been shown in the periodontal Ruffini endings, suggesting the involvement of brain-derived neurotrophin (BDNF), a ligand for TrkB, in the development and regeneration of this mechanoreceptor. Our recent studies using BDNF-deficient mice demonstrated a delayed in regeneration of the periodontal Ruffini endings, and furthermore suggested the involvement of neurotrophin-4/5 (NT-4/5) in their regeneration. Methods: NT-4/5 homozygous and wild-type mice were used in this study. The animals whose inferior alveolar nerve (IAN) was cut were processed for immunohistochemistry for protein gene product 9.5 (PGP 9.5), a general neuronal marker. The chronological neural density was calculated with a computer-assisted image analyzer. Results: In control group, without nerve injury, immunohistochemistry for PGP 9.5 demonstrated the presence of immature Ruffini endings in the periodontal ligament of the NT-4/5 (-/-) homozygous mice. We failed to find such typical Ruffini endings in the periodontal ligament of the homozygous mice: A majority of the periodontal Ruffini endings remained to show smooth outlines. At 3 days after nerve injury, the PGP 9.5-positive neural elements had completely disappeared in both types. They re-appeared in both animals at postoperative 7 days, and their regeneration has proceeded later with increasing of neural density in both types. Quantitative analysis demonstrated a constant lower neural density in the restricted area at each stage (>15% reduction) throughout experimental stages. However, the neural density in the NT-4/5 homozygous mice never recovered to the control level at postoperative 28 days when the periodontal Ruffini endings in the wild-type mice showed the same terminal morphology and neural density. Conclusions: These findings indicate that NT-4/5 is required for the regeneration of periodontal Ruffini endings after transection of the IAN. Supported by grants from JSPS (Nos. 16390522 and 17791519).