Brain-derived Neurotrophic Factor Stimulates Bone/Cementum-related Protein Gene Expression in Cementoblasts

Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku, Hiroshima 34-8553, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2008; 283(23):16259-67. DOI: 10.1074/jbc.M800668200
Source: PubMed


Brain-derived neurotrophic factor (BDNF), recognized as essential in the developing nervous system, is involved in differentiation
and proliferation in non-neuronal cells, such as endothelial cells, osteoblasts, and periodontal ligament cells. We have focused
on the application of BDNF to the regeneration of periodontal tissue and indicated that BDNF promotes the regeneration of
experimentally created periodontal defects. Cementoblasts form cementum, mineralized tissue, which is key to establishing
a functional periodontium. The application of BDNF to the regeneration of periodontal tissue requires elucidation of the mechanism
by which BDNF regulates the functions of cementoblasts. In this study, we examined how BDNF regulates the mRNA expression
of bone/cementum-related proteins (alkaline phosphatase (ALP), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2)) in cultures of immortalized human cementoblast-like (HCEM) cells. BDNF elevated the mRNA levels of ALP, OPN, and BMP-2 in HCEM cells. Small interfering RNA (siRNA) for TRKB, a high affinity receptor of BDNF, siRNA for ELK-1, which is a downstream target of ERK1/2, and PD98059, an ERK inhibitor, obviated the increase in the mRNA levels. BDNF increased
the levels of phosphorylated ERK1/2 and Elk-1, and the blocking of BDNF signaling by treatment with siRNA for TRKB and PD98059 suppressed the phosphorylation of ERK1/2 and Elk-1. Furthermore, BDNF increased the levels of phosphorylated
c-Raf, which activates the ERK signaling pathway. These findings provide the first evidence that the TrkB-c-Raf-ERK1/2-Elk-1
signaling pathway is required for the BDNF-induced mRNA expression of ALP, OPN, and BMP-2 in HCEM cells.

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    • "Concerning periodontal tissue regeneration, BDNF reportedly increased the synthesis of osteopontin, BMP-2, and collagen in human periodontal ligament (PDL) cells [10], strongly suggesting the existence of the Trk signaling pathway, which the receptor selectively binds to the BDNF [11]. It was further confirmed that a specific signaling pathway, TrkB-c-Raf-ERK1/2-Elk-1 was essential for the BDNF to induce mRNA expression of bone/cementum-related proteins [12] and also for the regulation of cementoblast survival [13]. In vivo application of this promising neurotrophic factor in a canine Class III furcation defect showed that BDNF can regenerate new alveolar bone, cementum, and connective fibers attached to the newly formed cementum [10], [14]. "
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    ABSTRACT: This study aimed to observe the regenerative effect of brain-derived neurotrophic factor (BDNF) in a non-human primate furcation defect model. Class II furcation defects were created in the first and second molars of 8 non-human primates to simulate a clinical situation. The defect was filled with either, Group A: BDNF (500 µg/ml) in high-molecular weight-hyaluronic acid (HMW-HA), Group B: BDNF (50 µg/ml) in HMW-HA, Group C: HMW-HA acid only, Group D: empty defect, or Group E: BDNF (500 µg/ml) in saline. The healing status for all groups was observed at different time-points with micro computed tomography. The animals were euthanized after 11 weeks, and the tooth-bone specimens were subjected to histologic processing. The results showed that all groups seemed to successfully regenerate the alveolar buccal bone, however, only Group A regenerated the entire periodontal tissue, i.e., alveolar bone, cementum and periodontal ligament. It is suggested that the use of BDNF in combination with a scaffold such as the hyaluronic acid in periodontal furcation defects may be an effective treatment option.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "BDNF is now recognized to be produced by a much wider variety of cell types, including vascular endothelial cells, leukocytes, adipocytes, and osteoblasts [8]–[10]. Studies showing that BDNF and TrkB are expressed in bone and cartilage, and that their expression is altered during bone healing, have implicated BDNF as a mediator of bone health [10], [20]–[23]. We have shown that TrkB is expressed in epiphyseal growth plate cartilage, and that BDNF positively regulates chondrocyte differentiation, suggesting that TrkB and BDNF also have a role in long bone growth. "
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    ABSTRACT: Long bone growth results from ordered chondrocyte development within the cartilagenous growth plate. Chondrocytes are recruited from a resting pool to proliferate along the long axis of the bone, until various signals trigger differentiation and hypertrophy. We have shown previously that the neurotrophin receptor TrkB is expressed in growth plate chondrocytes, where the tyrosine kinase receptor regulates the pace of hypertrophic differentiation by modulating the activities of ERK and p38 MAP kinases. To investigate the physiological relevance of TrkB to bone growth in vivo, we generated mice with a targeted disruption of the receptor, and compared them to mice targeted for MAPK14, the gene for p38α. The TrkB mutant and p38α mutant mice showed a similar degree of dwarfism and delayed hypertrophic differentiation. To extend these findings, we showed that both the TrkB and p38α mutant mice have altered expression of Runx2 and Sox9, two key transcription factors required for skeletogenesis. The data provides in vivo evidence for the role of TrkB in bone growth, supports the role of p38 downstream of TrkB, and suggests that Runx2 and Sox9 expression is regulated by this pathway at the growth plate.
    Preview · Article · Jun 2013 · PLoS ONE
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    • "Downstream mechanisms of BDNF signaling include the initiation of gene transcription. Known mediators of BDNF-regulated transcription include the cAMP response element binding protein (CREB) [14], [17] and the ternary complex factor (TFC) protein Elk-1 [18], [19]. The activities of these transcription factors are positively regulated by phosphorylation, which is a major mechanism of their conveying BDNF-stimulated responses. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression.
    Full-text · Article · Feb 2009 · PLoS ONE
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