title: GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway.
abstract: Osteoclasts are multinucleated cells that are formed by the fusion of mononuclear osteoclasts, which is an essential process in bone resorption leading to bone remodeling. Herein we show that GM-CSF promoted the fusion of prefusion osteoclasts (pOCs). The expression of GM-CSF receptor-alpha was significantly up-regulated at the fusion stage of pOCs induced by RANKL. GM-CSF induced the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which was mediated by inducing NFATc1 via induction of c-Fos. The expression of c-Fos and NFATc1 was regulated by the ERK signaling pathway. Inhibition of ERK and NFATc1 suppressed the expression of DC-STAMP and led to the fusion inhibition of pOC. However, retrovirus-mediated expression of NFATc1 in pOCs rescued the defect in pOC fusion, despite the presence of U0126 and cyclosporin A. GM-CSF-stimulated pOCs had an intact actin ring and could resorb bone. Importantly, pOCs infected with constitutively active MEK adenovirus expressed c-Fos and NFATc1, followed by the binding of NFATc1 to the DC-STAMP promoter, which enables its transcription and expression. Constitutively active MEK-infected pOCs are able to resorb bone by undergoing cell-cell fusion. Taken together, our results demonstrated that GM-CSF induced fusion of pOCs to form multinucleated osteoclasts, making the osteoclast capable of bone resorption.
authors.affiliation: Department of Rheumatology, School of Medicine, Wonkwang University, Iksan, Jeonbuk, Korea.
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Hun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Yeon
authors.forename: Sik-Won
authors.initials: SW
authors.lastname: Choi
authors.forename: Churl Hong
authors.initials: CH
authors.lastname: Chun
authors.forename: Han Bok
authors.initials: HB
authors.lastname: Kwak
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000821:virology; D001862:Bone Resorption / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002459:Cell Fusion; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000502:physiology; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000821:virology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: C499636:DC-STAMP protein, mouse; D006131:Growth Inhibitors; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins