Pim-1 regulates RANKL-induced osteoclastogenesis via NF-κB activation and NFATc1 induction.
Pim kinases are emerging as important mediators of cytokine signaling pathways in hematopoietic cells. In this study, we demonstrate that Pim-1 positively regulates RANKL-induced osteoclastogenesis and that Pim-1 expression can be upregulated by RANKL signaling during osteoclast differentiation. The silencing of Pim-1 by RNA interference or overexpression of a dominant negative form of Pim-1 (Pim-1 DN) in bone marrow-derived macrophage cells attenuates RANKL-induced osteoclast formation. Overexpression of Pim-1 DN blocks RANKL-induced activation of TGF-β-activated kinase 1 (TAK1) and NF-κB as well as expression of NFATc1 during osteoclastogenesis. However, we found that overexpression of TAK1 in the presence of Pim-1 DN rescues NF-κB activation. Additionally, Pim-1 interacts with RANK as well as TAK1, indicating that Pim-1 is involved in RANKL-induced NF-κB activation via TAK1. Furthermore, we demonstrate that Pim-1 also regulates NFATc1 transcription activity and subsequently induces osteoclast-associated receptor expression, an osteoclast-specific gene. Taken together, our results reveal that Pim-1 positively regulates RANKL-induced osteoclastogenesis.
National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Research Institute of Medical Sciences, Brain Korea 21, Chonnam National University Medical School, Gwangju, South Korea.
Kabsun
K
Kim
Jung Ha
JH
Kim
Bang Ung
BU
Youn
Hye Mi
HM
Jin
Nacksung
N
Kim
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D051573:Proto-Oncogene Proteins c-pim-1; D053245:RANK Ligand; D000099151:MAP Kinase Kinase Kinase 7; C494005:Nfatc1 protein, mouse; C505689:Tnfsf11 protein, mouse; C496636:Pim1 protein, mouse