title: Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation.
abstract: Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3β in osteoblasts is well characterized as a negative regulator of β-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3β inactivation upon receptor activator of NF-κB ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3β activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3β (GSK3β-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3β (GSK3β-K85R) or small interfering RNA (siRNA)-mediated GSK-3β silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3β further confirmed the negative role of GSK-3β in osteoclast formation. We also show that overexpression of the GSK3β-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3β-S9A mutant show an osteopetrotic phenotype due to impaired osteoclast differentiation. Further, osteoclast precursor cells from the transgenic mice show defects in expression and nuclear localization of NFATc1. These findings demonstrate a novel role for GSK-3β in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Hyun Duk
authors.initials: HD
authors.lastname: Jang
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Shin
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: Park
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Hong
authors.forename: Kwiyeom
authors.initials: K
authors.lastname: Yoon
authors.forename: Ryeojin
authors.initials: R
authors.lastname: Ko
authors.forename: Chang-Yong
authors.initials: CY
authors.lastname: Ko
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Daewon
authors.initials: D
authors.lastname: Jeong
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology*; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002118:Calcium