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Endocrinology Vol. 142, No. 3 1290-1295
Copyright © 2001 by The Endocrine Society

ARTICLES

Receptor Activator of Nuclear Factor-{kappa}B Ligand Activates Nuclear Factor-{kappa}B in Osteoclast Precursors1

Shi Wei, Steven L. Teitelbaum, Michael W.-H. Wang and F. Patrick Ross

Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: F. Patrick Ross, Ph.D., Department of Pathology, Washington University School of Medicine, Barnes-Jewish Hospital North Mail Stop #90–30-669, 216 South Kingshighway, St. Louis, Missouri 63110. E-mail: rossf{at}medicine.wustl.edu

Receptor activator of nuclear factor-{kappa}B ligand [RANK ligand (RANK-L)] stimulates mature osteoclasts to resorb bone, a process associated with NF-{kappa}B activation. RANK-L also prompts macrophages to develop the osteoclast phenotype. Although NF-{kappa}B is essential for osteoclast differentiation, it is not known whether RANK-L activates this transcription complex in osteoclast precursors. We report that RANK-L rapidly induces NF-{kappa}B activation in both authentic osteoclast precursors, namely bone marrow macrophages, and RAW 264.7 cells, a murine macrophage line also capable of RANK-L-mediated osteoclastogenesis. Supershift studies reveal the RANK-L-induced DNA binding moiety contains p50/p65, the most common NF-{kappa}B complex. Subcellular translocation of p50 and p65 subunits is confirmed by Western blots and immunofluorescence analysis. RANK-L activates NF-{kappa}B in both bone marrow macrophages and RAW 264.7 cells by serine phosphorylation of I{kappa}B{alpha} within 5 min, resulting in rapid I{kappa}B{alpha} degradation and resynthesis. Attesting to function, RANK-L treatment of RAW 264.7 cells transiently transfected with a plasmid containing NF-{kappa}B consensus elements linked to luciferase greatly enhances reporter activity. Our data suggest that activation of the NF-{kappa}B pathway is an integral component of RANK-L-induced osteoclast differentiation.




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