Processing of the NF-kappa B2 precursor p100 to p52 is critical for RANKL-induced osteoclast differentiation.
Gene targeting of the p50 and p52 subunits of NF-kappaB has shown that NF-kappaB plays a critical role in osteoclast differentiation. However, the molecular mechanism by which NF-kappaB regulates osteoclast differentiation is still unclear. To address this issue, we analyzed alymphoplasia (aly/aly) mice in which the processing of p100 to p52 does not occur owing to an inactive form of NF-kappaB-inducing kinase (NIK). Aly/aly mice showed a mild osteopetrosis with significantly reduced osteoclast numbers. RANKL-induced osteoclastogenesis from bone marrow cells of aly/aly mice also was suppressed. RANKL still induced the degradation of I kappaB alpha and activated classical NF-kappaB, whereas processing of p100 to p52 was abolished by the aly/aly mutation. Moreover, RANKL-induced expression of NFATc1 was impaired in aly/aly bone marrow. Overexpression of constitutively active IKK alpha or p52 restored osteoclastogenesis in aly/aly cells. Finally, transfection of either wild-type p100, p100 Delta GRR that cannot be processed to p52, or p52 into NF-kappaB 2-deficient cells followed by RANKL treatment revealed a strong correlation between the number of osteoclasts induced by RANKL and the ratio of p52 to p100 expression. Our data provide a new finding for a previously unappreciated role for NF-kappaB in osteoclast differentiation.
Maruyama
Toshimasa
T
Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, Fukuoka, Japan.
Fukushima
Hidefumi
H
Nakao
Kayoko
K
Shin
Masashi
M
Yasuda
Hisataka
H
Weih
Falk
F
Doi
Takahiro
T
Aoki
Kazuhiro
K
Alles
Neil
N
Ohya
Keiichi
K
Hosokawa
Ryuji
R
Jimi
Eijiro
E
D000818:Animals; D002454:Cell Differentiation; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D053245:RANK Ligand / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D050778:NFATC Transcription Factors; D017346:Protein Serine-Threonine Kinases; D053245:RANK Ligand; D000097782:NF-kappaB-Inducing Kinase; C494005:Nfatc1 protein, mouse; C496562:Ikbkb protein, mouse