title: PKR plays a positive role in osteoblast differentiation by regulating GSK-3β activity through a β-catenin-independent pathway.
abstract: Double-stranded RNA-dependent protein kinase (PKR) is involved in various cellular functions. We previously reported that PKR regulates osteoblast differentiation, but the specific mechanisms by which this occurs remain unclear. In this study, we investigated the role of PKR in Glycogen synthase kinase 3β (GSK-3β) regulation of osteoblast differentiation. Lithium chloride (LiCl), a GSK-3β inhibitor, increased GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. LiCl also inhibited Runx2 and expression of its regulated genes, causing inhibition of Alkaline phosphatase activity and mineralization. LiCl injection to the calvaria in mice suppressed bone formation. Further, GSK-3β phosphorylation was increased in osteoblasts, by Akt-independent mechanisms, in which PKR was constitutively inactivated. A PKR inhibitor, 2-aminopurine, also induced GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. Further, Runx2 and its regulated genes were inhibited in PKR-inactivated osteoblasts, and differentiation was suppressed through a β-catenin-independent pathway. PKR positively regulates the differentiation of osteoblasts by mediating GSK-3β activity through a β-catenin-independent pathway.
authors.affiliation: Department of Fundamental Oral Health Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto, Tokushima, Japan. kaya@dent.tokushima-u.ac.jp
authors.forename: Kaya
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Okamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ochiai
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Haneji
authors.forename: Masami
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hinode
authors.forename: Hideo
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000187:drug effects / Q000254:growth & development; D051176:beta Catenin / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride