Monokine induced by interferon-γ is induced by receptor activator of nuclear factor κB ligand and is involved in osteoclast adhesion and migration

• Published in: Blood 2005-04, Vol.105 (7), p.2963-2969
• Main Authors: Kwak, Han Bok, Lee, Soo Woong, Jin, Hye Mi, Ha, Hyunil, Lee, Sang Ho, Takeshita, Sunao, Tanaka, Sakae, Kim, Hyun-Man, Kim, Hong-Hee, Lee, Zang Hee
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - metabolism; Cell Adhesion - physiology; Cell Differentiation - physiology; Cell Movement - physiology; Cells, Cultured; Chemokine CXCL9; Chemokines, CXC - genetics; Chemokines, CXC - metabolism; Combined treatment; DNA-Binding Proteins - metabolism; Gene Expression - physiology; Interferon-gamma - physiology; Macrophage Colony-Stimulating Factor - pharmacology; Medical sciences; Membrane Glycoproteins - metabolism; Mice; NF-kappa B - metabolism; Osteoclasts - cytology; Osteoclasts - physiology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Chemokine - genetics; Receptors, CXCR3; Serine - metabolism; STAT1 Transcription Factor; Stem Cells - cytology; Stem Cells - physiology; Trans-Activators - metabolism; Treatment. General aspects; Tumors; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-07-2534

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 κB (NF-κB) 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-γ (IFN-γ) (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-κB, 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.