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J. Biol. Chem., Vol. 283, Issue 23, 16259-16267, June 6, 2008

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

Mikihito Kajiya, Hideki Shiba¹, Tsuyoshi Fujita, Kazuhisa Ouhara, Katsuhiro Takeda, Noriyoshi Mizuno, Hiroyuki Kawaguchi, Masae Kitagawa, Takashi Takata^¶, Koichiro Tsuji^||, and Hidemi Kurihara

From the Department of Periodontal Medicine and ^¶Department of Oral Maxillofacial Pathobiology, Hiroshima University Graduate School of Biomedical Sciences, Center of Oral Clinical Examination, Hiroshima University Hospital, and ^||Two Cells Company Ltd., 1-2-3, Kasumi, Minami-ku, Hiroshima 34-8553, Japan

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.

Received for publication, January 25, 2008 , and in revised form, March 21, 2008.

^* This work was supported in part by Grant-in-aid for Scientific Research (B) 18390560 from the Japan Society for the Promotion of Science, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Tel.: 81-82-257-5663; Fax: 81-82-257-5664; E-mail: bashihi{at}hiroshima-u.ac.jp.

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