Brain-derived neurotrophic factor promotes orthodontic tooth movement by alleviating periodontal ligament stem cell senescence

Abstract

Orthodontic treatment in older adults is more difficult than in younger adults, partially due to delayed osteogenesis caused by senescence of human periodontal ligament stem cells (hPDLSCs). The production of brain-derived neurotrophic factor (BDNF) which regulates the differentiation and survival of stem cells decreases with age. We aimed to investigate the relationship between BDNF and hPDLSC senescence and its effects on orthodontic tooth movement (OTM). We constructed mouse OTM models using orthodontic nickel‑titanium springs and compared the responses of wild-type (WT) and BDNF+/− mice with or without addition of exogenous BDNF. In vitro, hPDLSCs subjected to the mechanical stretch were used to simulate the cell stretch environment during OTM. We extracted periodontal ligament cells from WT and BDNF+/− mice to evaluate their senescence-related indicators. The application of orthodontic force increased BDNF expression in the periodontium of WT mice, while the mechanical stretch increased BDNF expression in hPDLSCs. Osteogenesis-related indicators, including RUNX2 and ALP decreased and cellular senescence-related indicators such as p16, p53 and β-galactosidase increased in BDNF+/− mice periodontium. Furthermore, periodontal ligament cells extracted from BDNF+/− mice exhibited more senescent compared with cells from WT mice. Application of exogenous BDNF decreased the expression of senescence-related indicators in hPDLSCs by inhibiting Notch3, thereby promoting osteogenic differentiation. Periodontal injection of BDNF decreased the expression of senescence-related indicators in periodontium of aged WT mice. In conclusion, our study showed that BDNF promotes osteogenesis during OTM by alleviating hPDLSCs senescence, paving a new path for future research and clinical applications.