The Journal of Experimental Medicine
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Published 16 May 2005. doi:10.1084/jem.20042081
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 10, 1677-1687
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ARTICLE

 I{kappa}B kinase (IKK)ß, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

Maria Grazia Ruocco1, Shin Maeda1, Jin Mo Park1, Toby Lawrence1, Li-Chung Hsu1, Yixue Cao1, Georg Schett2, Erwin F. Wagner3, and Michael Karin1

1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093
2 Department of Internal Medicine III, Division of Rheumatology, University of Vienna, A-1090 Vienna, Austria
3 Research Institute of Molecular Pathology, A-1030 Vienna, Austria

CORRESPONDENCE Michael Karin: karinoffice{at}ucsd.edu

Transcription factor, nuclear factor {kappa}B (NF-{kappa}B), is required for osteoclast formation in vivo and mice lacking both of the NF-{kappa}B p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the I{kappa}B kinase (IKK) complex that mediate NF-{kappa}B activation, IKK{alpha} and IKKß, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKß subunit as a transducer of signals from receptor activator of NF-{kappa}B (RANK) to NF-{kappa}B. Although IKK{alpha} is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKß is required for osteoclastogenesis in vitro and in vivo. IKKß also protects osteoclasts and their progenitors from tumor necrosis factor {alpha}–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

Abbreviations used: H&E, hematoxylin-eosin; I{kappa}B, inhibitor of NF-{kappa}B; IKK, I{kappa}B kinase; M-CSF, macrophage-colony stimulating factor; NIK, NF-{kappa}B–inducing kinase; poly(IC), polyinosinic-polycytidylic acid; RANKL, receptor activator of NF-{kappa}B ligand; TNFR, TNF receptor; TRAP, tartrate-resistant acid phosphatase; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling.


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