title: PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β.
abstract: Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive. We now demonstrate that PKCβ acts as a positive regulator which inactivates glycogen synthase kinase-3β (GSK-3β) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKCβ expression is increased by RANKL. Pharmacological inhibition of PKCβ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-3β was decreased by PKCβ inhibition. Likewise, down-regulation of PKCβ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-3β phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the PKCβ pathway, leading to GSK-3β inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.
authors.affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea ; Present address: Department of Neurology, Seoul National University Hospital, and College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 110-749, Korea.
authors.forename: Hyunduk
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000628:therapy; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008301:Maleimides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D064546:Protein Kinase C beta / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012886:Skull / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007211:Indoles; D008301:Maleimides; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D034741:RNA, Small Interfering; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3; C070515:bisindolylmaleimide I
keywords: glycogen synthase kinase-3β; osteoclast differentiation; protein kinase Cβ; receptor activator of NF-κB ligand