These findings suggest that transplanted mesenchymal stem cells could survive and differentiate into periodontal tissue cells, resulting in enhancement of periodontal tissue regeneration.

To address whether brain-derived neurotrophic factor (BDNF) could be involved in periodontal tissue regeneration, we examined the effects of BDNF on proliferation and the expression of bone (cementum)- related proteins (osteopontin, bone morphogenetic protein [BMP]-2, type I collagen, alkaline phosphatase [ALPase], and osteocalcin) in cultures of human periodontal ligament (HPL) cells, which are thought to be prerequisite for periodontal tissue regeneration, and on proliferation and angiogenesis in human endothelial cells. Furthermore, we examined the effect of BDNF on the regeneration of periodontal tissues in experimentally induced periodontal defects in dogs. BDNF elevated the expression of ALPase and osteocalcin mRNAs and increased the synthesis of osteopontin, BMP-2, and type I collagen DNA in HPL cells. BDNF stimulated mRNA expression of vascular endothelial growth factor-B and tenascin-X, and proliferation and angiogenesis in human endothelial cells. In vivo studies showed that BDNF stimulated the formation of new alveolar bone cementum and connective new fibers, which were inserted into the newly formed cementum and bone. BDNF also stimulated blood capillary formation. These findings suggest that the regulation of functioning of periodontal ligament cells and endothelial cells by BDNF results in the promotion of periodontal tissue regeneration.

Brain-derived neurotrophic factor (BDNF), for which bovine collagen-derived atelocollagen is used as a scaffold, enhances periodontal tissue regeneration. However, a scaffold that does not contain unknown ingredients is preferable. Since the synthesized high-molecular-weight (HMW)-hyaluronic acid (HA) is safe and inexpensive, we evaluated the efficacy of HMW-HA as a BDNF scaffold. CD44, a major receptor of HA, was expressed in cultures of human periodontal ligament cells, and HMW-HA promoted the adhesion and proliferation of human periodontal ligament cells, although it did not influence the mRNA expression of bone (cementum)-related proteins. The in vitro release kinetics of BDNF from HMW-HA showed that BDNF release was sustained for 14 days. Subsequently, we examined the effect of BDNF/HMW-HA complex on periodontal tissue regeneration in dogs. A greater volume of newly formed alveolar bone and a longer newly formed cementum were observed in the BDNF/HMW-HA group than in the HMW-HA group, suggesting that HMW-HA assists the regenerative capacity of BDNF, although HMW-HA itself does not enhance periodontal tissue regeneration. Neither the poly (lactic-co-glycolic acid) group nor the BDNF/poly (lactic-co-glycolic acid) group enhanced periodontal tissue regeneration. In conclusion, HMW-HA is an adequate scaffold for the clinical application of BDNF.

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Brain-derived neurotrophic factor (BDNF) promotes the regeneration of periodontal tissue. Since angiogenesis is important for tissue regeneration, investigating effect of BDNF on endothelial cell function may help to reveal its mechanism, whereby, BDNF promotes periodontal tissue regeneration. In this study, we examined the influence of BDNF on migration in human microvascular endothelial cells (HMVECs), focusing on the effects on extracellular signal-regulated kinase (ERK), integrin α(V)β(3), and focal adhesion kinase (FAK). The migration of endothelial cells was assessed with a modified Boyden chamber and a wound healing assay. The expression of integrin α(V)β(3) and the phosphorylation of ERK and FAK were analyzed by immunoblotting and immunofluorescence microscopy. BDNF (25 ng/ml) induced cell migration. PD98059, an ERK inhibitor, K252a, a specific inhibitor for TrkB, a high affinity receptor of BDNF, and an anti-integrin α(V)β(3) antibody suppressed the BDNF-induced migration. BDNF increased the levels of integrin α(V)β(3) and phosphorylated ERK1/2 and FAK. The ERK inhibitor and TrkB inhibitor also reduced levels of integrin α(V)β(3) and phosphorylated FAK. We propose that BDNF stimulates endothelial cell migration by a process involving TrkB/ERK/integrin α(V)β(3)/FAK, and this may help to enhance the regeneration of periodontal tissue.