title: Monokine induced by interferon-gamma is induced by receptor activator of nuclear factor kappa B ligand and is involved in osteoclast adhesion and migration.
abstract: Bone remodeling is accompanied by the differentiation of osteoclasts from the monocyte/macrophage lineage of hematopoietic cells. The osteoclast differentiation process requires receptor activator of nuclear factor kappa B (NF-kappa B) ligand (RANKL), which causes complex changes in the expression of various genes. In a cDNA microarray study to identify genes targeted by RANKL, we found that monokine induced by the interferon-gamma (IFN-gamma) (MIG) gene was up-regulated in osteoclast precursor cells. The increase in MIG expression by RANKL was confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. RANKL induction of MIG required the activity of NF-kappa B, whose binding site is present in the MIG promoter. MIG induction by RANKL was also dependent on p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1). RANKL stimulated the phosphorylation of Ser727 of STAT1, which required p38 activity. MIG secreted on RANKL treatment could stimulate the migration and adhesion of osteoclast precursors and osteoclasts that were primed to express CXCR3, the MIG receptor, by macrophage-colony-stimulating factor (M-CSF). Therefore, we provide the first evidence demonstrating that RANKL stimulates the serine phosphorylation of STAT1 through the p38 MAPK pathway, causing MIG gene transcription and secretion, which may have a role in recruiting CXCR3-positive osteoclast precursors and osteoclasts to bone remodeling or inflammatory sites.
authors.affiliation: National Research Laboratory for Bone Metabolism, College of Dentistry, Chosun University, Gwangju, Korea.
authors.forename: Han Bok
authors.initials: HB
authors.lastname: Kwak
authors.forename: Soo Woong
authors.initials: SW
authors.lastname: Lee
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Jin
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Sunao
authors.initials: S
authors.lastname: Takeshita
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hyun-Man
authors.initials: HM
authors.lastname: Kim
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D010766:Phosphorylation; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015534:Trans-Activators; D012694:Serine; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases