GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway.
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.
Lee
Myeung Su
MS
Department of Rheumatology, School of Medicine, Wonkwang University, Iksan, Jeonbuk, Korea.
Kim
Hun Soo
HS
Yeon
Jeong-Tae
JT
Choi
Sik-Won
SW
Chun
Churl Hong
CH
Kwak
Han Bok
HB
Oh
Jaemin
J
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
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