The Journal of Experimental Medicine
StemCell Technologies
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Published online 25 August 2003 doi:10.1084/jem.20030116
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© Rockefeller University Press, 0022-1007/2003/9/771 $5.00
The Journal of Experimental Medicine, Volume 198, Number 5, 771-781

The I{kappa}B Function of NF-{kappa}B2 p100 Controls Stimulated Osteoclastogenesis

Deborah Veis Novack1,2, Li Yin1, Amanda Hagen-Stapleton1, Robert D. Schreiber1, David V. Goeddel3, F. Patrick Ross1 and Steven L. Teitelbaum1

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
2 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
3 Tularik, Inc., South San Francisco, CA 94080

Address correspondence to Deborah Veis Novack, Washington University School of Medicine, 660 S. Euclid Ave., Box 8301, St. Louis, MO 63110. Phone: (314) 454-8472; Fax: (314) 454-5047; email: novack{at}wustl.edu

The prototranscription factor p100 represents an intersection of the NF-{kappa}B and I{kappa}B families, potentially serving as both the precursor for the active NF-{kappa}B subunit p52 and as an I{kappa}B capable of retaining NF-{kappa}B in the cytoplasm. NF-{kappa}B–inducing kinase (NIK) controls processing of p100 to generate p52, and thus NIK-deficient mice can be used to examine the biological effects of a failure in such processing. We demonstrate that treatment of wild-type osteoclast precursors with the osteoclastogenic cytokine receptor activator of NF-{kappa}B ligand (RANKL) increases both expression of p100 and its conversion to p52, resulting in unchanged net levels of p100. In the absence of NIK, p100 expression is increased by RANKL, but its conversion to p52 is blocked, leading to cytosolic accumulation of p100, which, acting as an I{kappa}B protein, binds NF-{kappa}B complexes and prevents their nuclear translocation. High levels of unprocessed p100 in osteoclast precursors from NIK-/- mice or a nonprocessable form of the protein in wild-type cells impair RANKL-mediated osteoclastogenesis. Conversely, p100-deficient osteoclast precursors show enhanced sensitivity to RANKL. These data demonstrate a novel, biologically relevant means of regulating NF-{kappa}B signaling, with upstream control and kinetics distinct from the classical I{kappa}B{alpha} pathway.

Key Words: mice knockout • bone remodeling/physiology • MAP kinase kinase kinases • cultured cells/physiology • murine RANKL


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