Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis.
Bone homeostasis depends on the coordination of osteoclastic bone resorption and osteoblastic bone formation. Receptor activator of NF-kappaB ligand (RANKL) induces osteoclast differentiation through activating a transcriptional program mediated by the key transcription factor nuclear factor of activated T cells (NFAT) c1. Immunoreceptors, including osteoclast-associated receptor (OSCAR) and triggering receptor expressed by myeloid cells (TREM)-2, constitute the co-stimulatory signals required for RANKL-mediated activation of calcium signaling, which leads to the activation of NFATc1. However, it remains unknown whether the expression of immunoreceptors are under the control of NFATc1. Here we demonstrate that the expression of OSCAR, but not that of TREM-2, is up-regulated during osteoclastogenesis and markedly suppressed by the calcineurin inhibitor FK506, suggesting that OSCAR is transcriptionally regulated by NFATc1. NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF). We further provide evidence that NFATc1 specifically regulates OSCAR by chromatin immunoprecipitation assay and quantification of OSCAR and TREM-2 mRNA in NFATc1-/- cells. Thus, OSCAR but not TREM-2 is involved in the positive feedback loop of the immunoreceptor-NFATc1 pathway during osteoclastogenesis. Although several immunoreceptors have been identified as co-stimulatory molecules for RANKL, the expression and function are differentially regulated. These mechanisms, possibly together with the delicate regulation of their ligands on osteoblasts, may provide the exquisite machinery for the modulation of osteoclastogenesis in the maintenance of bone homeostasis.
Kim
Yoonji
Y
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549.
Sato
Kojiro
K
Asagiri
Masataka
M
Morita
Ikuo
I
Soma
Kunimichi
K
Takayanagi
Hiroshi
H
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018920:Coculture Techniques; D005434:Flow Cytometry; D047468:Immunoprecipitation; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D053245:RANK Ligand; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry; D014158:Transcription, Genetic; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D000099232:Proto-Oncogene Protein Spi-1
D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D002843:Chromatin; D008024:Ligands; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D012313:RNA; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D016559:Tacrolimus; D015534:Trans-Activators; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D000099232:Proto-Oncogene Protein Spi-1; C512828:OSCAR protein, human; C450519:Oscar protein, mouse; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C408842:TREM1 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse