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Processing of the NF‐κB2 precursor p100 to p52 is critical for RANKL‐induced osteoclast differentiation
Author(s) -
Maruyama Toshimasa,
Fukushima Hidefumi,
Nakao Kayoko,
Shin Masashi,
Yasuda Hisataka,
Weih Falk,
Doi Takahiro,
Aoki Kazuhiro,
Alles Neil,
Ohya Keiichi,
Hosokawa Ryuji,
Jimi Eijiro
Publication year - 2010
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.091032
Subject(s) - rankl , osteoclast , nf κb , nfkb1 , bone marrow , medicine , iκb kinase , kinase , endocrinology , chemistry , transfection , microbiology and biotechnology , biology , cancer research , signal transduction , cell culture , transcription factor , gene , receptor , biochemistry , activator (genetics) , genetics
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. © 2010 American Society for Bone and Mineral Research