The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis.
Notch signaling plays a key role in various cell differentiation processes including bone homeostasis. However, the specific involvement of Notch in regulating osteoclastogenesis is still controversial. In the present study, we show that RANKL induces expression of Jagged1 and Notch2 in bone marrow macrophages during osteoclast differentiation. Suppression of Notch signaling by a selective gamma-secretase inhibitor or Notch2 short hairpin RNA suppresses RANKL-induced osteoclastogenesis. In contrast, induction of Notch signaling by Jagged1 or by ectopic expression of intracellular Notch2 enhances NFATc1 promoter activity and expression and promotes osteoclastogenesis. Finally, we found that Notch2 and p65 interact in the nuclei of RANKL-stimulated cells and that both proteins are recruited to the NFATc1 promoter, driving its expression. Taken together, our results show a new molecular cross talk between Notch and NF-kappaB pathways that is relevant in osteoclastogenesis.
Fukushima
Hidefumi
H
Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan. r07fukushima@fa.kyu-dent.ac.jp
Nakao
Akihiro
A
Okamoto
Fujio
F
Shin
Masashi
M
Kajiya
Hiroshi
H
Sakano
Seiji
S
Bigas
Anna
A
Jimi
Eijiro
E
Okabe
Koji
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
D008024:Ligands; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C497765:Notch2 protein, mouse; D009842:Oligopeptides; D053245:RANK Ligand; D012333:RNA, Messenger; D051883:Receptor, Notch2; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal