TY - JOUR
T1 - Dimer formation of receptor activator of nuclear factor κB induces incomplete osteoclast formation
AU - Iwamoto, Katsuya
AU - Miyamoto, Takeshi
AU - Sawatani, Yumi
AU - Hosogane, Naobumi
AU - Hamaguchi, Isao
AU - Takami, Masamichi
AU - Nomiyama, Kana
AU - Takagi, Katsumasa
AU - Suda, Toshio
N1 - Funding Information:
This work was supported by research grants from the Japan Society for the Promotion of Science (JSPS) and from the Ministry of Education, Culture of Japan. T. Miyamoto is a young scientist in the JSPS fellowship program.
PY - 2004/12/3
Y1 - 2004/12/3
N2 - Receptor activator of nuclear factor κB-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.
AB - Receptor activator of nuclear factor κB-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.
KW - Differentiation
KW - FKBP36v
KW - NFATc1
KW - Osteoclast
KW - RANK
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U2 - 10.1016/j.bbrc.2004.10.024
DO - 10.1016/j.bbrc.2004.10.024
M3 - Article
C2 - 15522223
AN - SCOPUS:7444266794
VL - 325
SP - 229
EP - 234
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -