Effect of Brain-Derived Neurotrophic Factor on the Neurogenesis and Osteogenesis in Bone Engineering.

Abstract

During bone growth, the lack of a neuralized vascular network in the regenerating area can affect subsequent bone quality. This study aimed to investigate if brain-derived neurotrophic factor (BDNF) could promote neurogenesis and osteogenesis in human bone mesenchymal stem cells (hBMSCs) to improve bone formation during tissue engineering. Initially, a safe and effective BDNF concentration that facilitated hBMSC proliferation in vitro was determined. Subsequently, examination of mineralized nodule formation and evaluation of alkaline phosphatase (ALP) activity and ALP gene expression revealed that the most effective concentration of BDNF to elicit a response in hBMSCs was 100 ng/mL. In addition, we found out that by binding with TrkB receptor, the downstream Erk1/2 was phosphorylated, which promoted the expression of transcription factors, such as Runx2 and Osterix that are associated with osteoblast differentiation. We also found that by day 7 post-treatment, the neurogenic biomarkers, p75 and s100, were highly expressed in 100 ng/mL BDNF-treated hBMSCs. Finally, the effects of BDNF on osteogenesis and neurogenesis in newly formed tissues were assessed using animal models with a β-tricalcium phosphate scaffold. This revealed that treatment with 100 ng/mL BDNF promoted the osteogenesis and neurogenesis of hBMSCs in vivo by increasing expression of the osteogenic marker osteocalcin and various neurogenic biomarkers, including microtubule-associated protein 2, glial fibrillary acidic protein, neural/glial antigen 2, and β-tubulin III. This study has demonstrated that BDNF promotes hBMSC osteogenesis and neurogenesis in vitro and in vivo, and that BDNF may indirectly promote osteogenesis through increased neurogenesis. This further suggests that encouraging neutralization during bone engineering will lead to effective repairing of bone defects. The study may also provide insight into related fields, such as osseoperception and stress feedback regulation after dental implantation.