Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 11, Pages 7349-7361Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.538314
Keywords
Bone; NF-kappaB; Osteoclast; Phosphorylation; Signal Transduction
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [23390424, 23593039, 24890214]
- Grants-in-Aid for Scientific Research [24791980, 23390424, 23593039, 24890214] Funding Source: KAKEN
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Background: The alternative NF-B pathway plays important roles in osteoclastogenesis through an unknown mechanism. Results: RelB-induced Cot expression rescues RANKL-induced osteoclastogenesis in cells isolated from aly/aly mice, which lack active NIK. Conclusion: The overexpression of RelB rescues RANKL-induced osteoclastogenesis by Cot/IKK-induced NF-B2 processing in aly/aly cells. Significance: The Akt/Cot/IKK pathway that is induced by RelB contributes to RANKL-induced osteoclastogenesis by activating the alternative NF-B pathway. The alternative nuclear factor-B (NF-B) pathway, mainly the RelB-p52 heterodimer, plays important roles in bone metabolism through an unknown mechanism. We have previously reported that alymphoplasia (aly/aly) mice, which lack active NF-B-inducing kinase (NIK), show mild osteopetrosis due to the inhibition of osteoclastogenesis. p100 retains RelB in the cytoplasm and inhibits RANKL-induced osteoclastogenesis in aly/aly cells. Furthermore, the overexpression of RelB in aly/aly cells rescues RANKL-induced osteoclastogenesis by inducing p100 processing. In contrast, the overexpression of p65 in aly/aly cells has no effect. However, the overexpression of RelB fails to rescue RANKL-induced osteoclastogenesis in the presence of p100GRR, which cannot be processed to p52, suggesting that p100 processing is a key step in RelB-rescued, RANKL-induced osteoclastogenesis in aly/aly cells. In this study, Cot (cancer Osaka thyroid), an MAP3K, was up-regulated by RelB overexpression. Analysis of the Cot promoter demonstrated that p65 and RelB bound to the distal NF-B-binding site and that RelB but not p65 bound to the proximal NF-B-binding site in the Cot promoter. The knocking down of Cot expression significantly reduced the RANKL-induced osteoclastogenesis induced by RelB overexpression. The phosphorylation of IKK at threonine 23 and its kinase activity were indispensable for the processing of p100 and osteoclastogenesis by RelB-induced Cot. Finally, constitutively activated Akt enhanced osteoclastogenesis by RelB-induced Cot, and a dominant-negative form of Akt significantly inhibited it. Taken together, these results indicate that the overexpression of RelB restores RANKL-induced osteoclastogenesis by activation of Akt/Cot/IKK-induced p100 processing.
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