title: The Transcription Factor EB (TFEB) Regulates Osteoblast Differentiation Through ATF4/CHOP-Dependent Pathway.
abstract: Osteoblasts are bone-forming cells that produce large amounts of collagen type I and various bone matrix proteins. Although osteoblast differentiation is highly regulated by various factors, it remains unknown whether lysosomes are directly involved in osteoblast differentiation. Here, we demonstrate the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, modulates osteoblast differentiation. The expression levels of TFEB as well as those of endosomal/lysosomal proteins were up-regulated during osteoblast differentiation using mouse osteoblastic MC3T3-E1 cells. By gene knockdown (KD) experiments with small interfering RNA (siRNA), TFEB depletion caused markedly reduced osteoblast differentiation as compared with the control cells. Conversely, overexpression (OE) of TFEB resulted in strikingly enhanced osteoblastogenesis compared to the control cells. By analysis of down-stream effector molecules, TFEB KD was found to cause marked up-regulation of activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP), both of which are essential factors for osteoblastogenesis. In contrast, TFEB OE promoted osteoblast differentiation through reduced expression of ATF4 and CHOP without differentiation agents. Given the importance of ATF4 and CHOP in osteoblastogenesis, it is clear that the TFEB-regulated signaling pathway for osteoblast differentiation is involved in ATF4/CHOP-dependent signaling pathway.
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.|Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Yoneshima
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakai
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nishishita
authors.affiliation: Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
mesh_terms: D016475:3T3 Cells; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C081452:Atf4 protein, mouse; C525718:BMP2 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D055396:Bone Morphogenetic Protein 2; C497250:Ddit3 protein, mouse; D017382:Reactive Oxygen Species; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; C484068:Tcfeb protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP