title: Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways.
abstract: Although melatonin has a variety of biological actions such as antitumor, antiangiogenic, and antioxidant activities, the osteogenic mechanism of melatonin still remains unclear. Thus, in the present study, the molecular mechanism of melatonin was elucidated in the differentiation of mouse osteoblastic MC3T3-E1 cells. Melatonin enhanced osteoblastic differentiation and mineralization compared to untreated controls in preosteoblastic MC3T3-E1 cells. Also, melatonin increased wound healing and dose-dependently activated osteogenesis markers such as runt-related transcription factor 2 (Runx2), osteocalcin (OCN), bone morphogenic protein (BMP)-2 and -4 in MC3T3-E1 cells. Of note, melatonin activated Wnt 5 α/β, β-catenin and the phosphorylation of c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in a time-dependent manner while it attenuated phosphorylation of glycogen synthase kinase 3 beta (GSK-3β) in MC3T3-E1 cells. Consistently, confocal microscope observation revealed that BMP inhibitor Noggin blocked melatonin-induced nuclear localization of β-catenin. Furthermore, Western blotting showed that Noggin reversed activation of β-catenin and Wnt5 α/β and suppression of GSK-3β induced by melatonin in MC3T3-E1 cells, which was similarly induced by ERK inhibitor PD98059. Overall, these findings demonstrate that melatonin promotes osteoblastic differentiation and mineralization in MC3T3-E1 cells via the BMP/ERK/Wnt pathways.
authors.affiliation: Department of Orthodondritics, Kyung-Hee University College of Dental Medicine, Seoul, Korea.
authors.forename: Ki-Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Kang
authors.forename: Eun-Man
authors.initials: EM
authors.lastname: Lee
authors.forename: Jae Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Minseok
authors.initials: M
authors.lastname: Kim
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Young Guk
authors.initials: YG
authors.lastname: Park
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D000975:Antioxidants; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D008550:Melatonin; D015675:Osteocalcin; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C493716:Runx2 protein, mouse; C438615:Wnt5a protein, mouse; C468567:Wnt5b protein, mouse; C000605507:Gsk3b protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one