title: Dimer formation of receptor activator of nuclear factor kappaB induces incomplete osteoclast formation.
abstract: Receptor activator of nuclear factor kappaB-ligand (RANKL) transduces a differentiation signal appropriate to osteoclasts likely through induction a receptor homotrimer; however, biological importance of RANK-trimerizarion is unknown. To address the signaling mechanism of the RANK receptor, we analyzed the effect of two different types of homodimer inducers RANK-TM-FKBP36v and hEpoR-RANK-TM on osteoclastogenesis. Dimerizing component FKBP36v or extracellular portion of human erythropoietin receptor (hEpoR) was fused to RANK lacking the extracellular domain, and the dimerization of this fusion protein was induced by addition of the chemical inducer of dimerization AP20187 or erythropoietin, respectively. Such treatment resulted in induction of TRAP-activity, a marker of osteoclast in a dose dependent manner, with an efficiency equivalent to that of induction by RANKL. However, dimerized-RANK-induced osteoclasts showed relatively low levels of multinucleation, pit forming activity, and expression of calcitonin receptor and cathepsin K, compared with osteoclasts which were induced in the presence of RANKL. As expression of nuclear factor of activated T cells 1 (NFATc1) was also reduced in dimerized-RANK-induced osteoclasts, RANK oligomerization by RANKL is a critical event to generate fully matured osteoclasts through upregulation of NFATc1.
authors.affiliation: Department of Cell Differentiation, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iwamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sawatani
authors.forename: Naobumi
authors.initials: N
authors.lastname: Hosogane
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.forename: Kana
authors.initials: K
authors.lastname: Nomiyama
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Takagi
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D015415:Biomarkers; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C463061:AP20187; D015415:Biomarkers; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D004921:Erythropoietin; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus