title: BDNF mimetic compound LM22A-4 regulates cementoblast differentiation via the TrkB-ERK/Akt signaling cascade.
abstract: Brain-derived neurotrophic factor (BDNF) activates its receptor TrkB, and promotes neuronal survival, differentiation, and synaptic functions. Furthermore, we have revealed that BDNF can also regulate cementoblast differentiation and cellular survival via TrkB-ERK/Akt signaling cascade, which, in turn, results in the induction of periodontal tissue regeneration. Recently, using in silico screening with a BDNF loop-domain pharmacophore, a small molecule BDNF mimetic, called LM22A-4 that can facilitate TrkB signaling in hippocampal neurons to prevent cell death, was identified. Therefore, this study aimed to investigate the effect of LM22A-4 on cementoblast differentiation and its molecular mechanism. LM22A-4 and BDNF stimulation was found to enhance OPN, ALPase, and OC mRNA expression in immortalized human cementoblast-like (HCEM) cells, indicating cementoblast differentiation. In addition, similar to this result, both LM22A-4 and BDNF treatment facilitated TrkB phosphorylation and TrkB binding to adaptor proteins, such as Shc, GRB2, and SOS1, indicating TrkB activation. Importantly, the downstream target ERK and Akt was also phosphorylated by LM22A-4 and BDNF stimulation. Moreover, BDNF mimetic stimulation transactivated ERK from the cytoplasm into the nuclei in HCEM cells. It is noteworthy that a tyrosine kinase receptor inhibitor, K252a, an MEK-ERK inhibitor (U0126), and a PI3Kinase-Akt inhibitor (LY294002) remarkably attenuated TrkB, ERK, and Akt phosphorylation as well as increase of OPN mRNA expression in the HCEM cells, respectively. These findings suggest that the small molecule BDNF mimetic LM22A-4 regulates cementoblast differentiation via the TrkB-ERK/Akt signaling cascade. Therefore, this small compound may lead to the development of a novel therapeutic approach for periodontal tissue regeneration.
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan. Electronic address: mkajiya@hiroshima-u.ac.jp.
authors: Mikihito
authors: M
authors: Kajiya
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Kei
authors: K
authors: Takeshita
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Mizuho
authors: M
authors: Kittaka
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Shinji
authors: S
authors: Matsuda
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Kazuhisa
authors: K
authors: Ouhara
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Katsuhiro
authors: K
authors: Takeda
authors: Department of Oral and Maxillofacial Pathology, Basic life Sciences, Institute of Biomedical and Health Science, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Takashi
authors: T
authors: Takata
authors: Center of Oral Clinical Examination, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Masae
authors: M
authors: Kitagawa
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Tsuyoshi
authors: T
authors: Fujita
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Hideki
authors: H
authors: Shiba
authors: Department of Periodontal Medicine, Applied life Sciences, Institute of Biomedical & Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors: Hidemi
authors: H
authors: Kurihara
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003739:Dental Cementum / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053495:Osteopontin / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*
chemical_list: D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; C585903:N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide; D012333:RNA, Messenger; D053495:Osteopontin; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; BDNF mimetic LM22A-4; ERK; OPN; TrkB