脑源性神经营养因子(BDNF)不仅对于神经系统发育是不可缺少的，而且还参与了多种非神经细胞如内皮细胞、成骨细胞和牙周膜细胞的分化和增殖。我们将BDNF应用于牙周组织再生的研究，发现BDNF可以促进牙周缺损模型的组织再生。成牙骨质细胞分泌形成矿化的牙骨质对于建立功能化的牙周组织有重要作用。阐释BDNF对成牙骨质细胞的调控机理对于其在牙周再生中的应用至关重要。此实验中我们研究BDNF如何影响永生化的人成牙骨质细胞(HCEM)样细胞骨/牙骨质相关蛋白基因的表达如ALPase、OPN、BMP-2 mRNA的表达，发现BDNF可增强这些mRNA的表达，而trkB(一种BDNF的高亲和力受体)、Elk-1(一种ERK1/2的下游靶标)的siRNA和PD98059(一种ERK抑制剂)均可阻止上述mRNA的表达升高。BDNF可增高磷酸化ERK1/2和Elk-1的表达，应用trkB或PD98059的siRNA阻止BDNF作用则阻止了这种磷酸化作用。我们进一步发现BDNF增强了磷酸化的c-Raf的水平，以此激活ERK信号通路。此研究首次证实了trkB-c-Raf-ERK1/2-Elk-1通路对于BDNF诱导的ALPase、OPN、和BMP-2增高的必要作用。

J Biol Chem. 2008 Apr 3 [Epub ahead of print]
    Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts.

    Kajiya M, Shiba H, Fujita T, Ouhara K, Takeda K, Mizuno N, Kawaguchi H, Kitagawa M, Takata T, Tsuji K, Kurihara H.

    Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553.

    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 the present study, we examined how BDNF regulates the mRNA expression of bone/cementum-related proteins (alkaline phosphatase (ALPase), osteopontin (OPN) and bone morphogenetic protein (BMP)-2) in cultures of immortalized human cementoblast-like (HCEM) cells. BDNF elevated the mRNA levels of ALPase, OPN, and BMP-2 in HCEM cells. 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 ALPase, OPN, and BMP-2 in HCEM cells.