Processing of the NF-κB2 precursor p100 to p52 is critical for RANKL-induced osteoclast differentiation

Toshimasa Maruyama, Hidefumi Fukushima, Kayoko Nakao, Masashi Shin, Hisataka Yasuda, Falk Weih, Takahiro Doi, Kazuhiro Aoki, Neil Alles, Keiichi Ohya, Ryuji Hosokawa, Eijiro Jimi

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Abstract

Gene targeting of the p50 and p52 subunits of NF-κB has shown that NF-κB plays a critical role in osteoclast differentiation. However, the molecular mechanism by which NF-κB 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-κB-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 IκBα and activated classical NF-κB, 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 IKKα or p52 restored osteoclastogenesis in aly/aly cells. Finally, transfection of either wild-type p100, p100ΔGRR that cannot be processed to p52, or p52 into NF-κB2-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-κB in osteoclast differentiation.

Original languageEnglish
Pages (from-to)1058-1067
Number of pages10
JournalJournal of Bone and Mineral Research
Volume25
Issue number5
DOIs
Publication statusPublished - May 1 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Maruyama, T., Fukushima, H., Nakao, K., Shin, M., Yasuda, H., Weih, F., Doi, T., Aoki, K., Alles, N., Ohya, K., Hosokawa, R., & Jimi, E. (2010). Processing of the NF-κB2 precursor p100 to p52 is critical for RANKL-induced osteoclast differentiation. Journal of Bone and Mineral Research, 25(5), 1058-1067. https://doi.org/10.1359/jbmr.091032