Dimer formation of receptor activator of nuclear factor kappaB induces incomplete osteoclast formation

Katsuya Iwamoto; Takeshi Miyamoto; Yumi Sawatani; Naobumi Hosogane; Isao Hamaguchi; Masamichi Takami; Kana Nomiyama; Katsumasa Takagi; Toshio Suda

doi:10.1016/j.bbrc.2004.10.024

Dimer formation of receptor activator of nuclear factor kappaB induces incomplete osteoclast formation

Biochem Biophys Res Commun. 2004 Dec 3;325(1):229-34. doi: 10.1016/j.bbrc.2004.10.024.

Authors

Katsuya Iwamoto¹, Takeshi Miyamoto, Yumi Sawatani, Naobumi Hosogane, Isao Hamaguchi, Masamichi Takami, Kana Nomiyama, Katsumasa Takagi, Toshio Suda

Affiliation

¹ Department of Cell Differentiation, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

PMID: 15522223
DOI: 10.1016/j.bbrc.2004.10.024

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Differentiation / physiology*
Cell Line
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Dimerization
Erythropoietin / pharmacology
Humans
Macrophages / cytology
Macrophages / drug effects
Macrophages / physiology
Membrane Glycoproteins / chemistry*
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Mice
NFATC Transcription Factors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Osteoclasts / cytology
Osteoclasts / physiology*
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Erythropoietin / genetics
Receptors, Erythropoietin / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Signal Transduction / physiology*
Tacrolimus / analogs & derivatives*
Tacrolimus / pharmacology
Tacrolimus Binding Proteins / genetics
Tacrolimus Binding Proteins / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

AP20187
Biomarkers
Carrier Proteins
DNA-Binding Proteins
Membrane Glycoproteins
NFATC Transcription Factors
NFATC1 protein, human
Nfatc1 protein, mouse
Nuclear Proteins
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Erythropoietin
Recombinant Fusion Proteins
TNFRSF11A protein, human
TNFSF11 protein, human
Tnfrsf11a protein, mouse
Tnfsf11 protein, mouse
Transcription Factors
Erythropoietin
Tacrolimus Binding Proteins
Tacrolimus