IL-3 acts directly on osteoclast precursors and irreversibly inhibits receptor activator of NF-kappa B ligand-induced osteoclast differentiation by diverting the cells to macrophage lineage.
Osteoclasts, the multinucleated cells that resorb bone, differentiate from hemopoietic precursors of the monocyte/macrophage lineage in the presence of M-CSF and receptor activator of NF-kappaB ligand (RANKL). In this study we investigated the role of IL-3 in osteoclast differentiation. We show here that IL-3, a cytokine secreted by activated T lymphocytes, inhibits RANKL-induced osteoclast differentiation by a direct action on early osteoclast precursors. Anti-IL-3 Ab neutralized the inhibitory effect of IL-3 on osteoclast differentiation. In addition, IL-3 inhibits TNF-alpha-induced osteoclast differentiation in bone marrow-derived macrophages. However, IL-3 has no inhibitory effect on mature osteoclasts. In osteoclast precursors, IL-3 prevents RANKL-induced nuclear translocation of NF-kappaB by inhibiting the phosphorylation and degradation of IkappaB. RT-PCR analysis revealed that IL-3 down-regulated c-Fos transcription. Interestingly, the osteoclast precursors in the presence of IL-3 showed strong expression of macrophage markers such as Mac-1, MOMA-2, and F4/80. Furthermore, the inhibitory effect of IL-3 on osteoclast differentiation was irreversible, and the osteoclast precursors preincubated in IL-3 were resistant to RANKL action. Thus, our results reveal for the first time that IL-3 acts directly on early osteoclast precursors and irreversibly blocks RANKL-induced osteoclast differentiation by diverting the cells to macrophage lineage.
Khapli
Shruti M
SM
National Center for Cell Science, Pune, India.
Mangashetti
Latha S
LS
Yogesha
S D
SD
Wani
Mohan R
MR
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007377:Interleukin-3 / Q000502:physiology*; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology*; D053244:Osteoprotegerin; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1
D002352:Carrier Proteins; D006023:Glycoproteins; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; D007377:Interleukin-3; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D016186:Receptor, Macrophage Colony-Stimulating Factor; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000099232:Proto-Oncogene Protein Spi-1; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse