The Journal of Experimental Medicine
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Published 6 September 2005. doi:10.1084/jem.20050978
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 5, 589-595
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BRIEF DEFINITIVE REPORT

 Osteoclast differentiation independent of the TRANCE–RANK–TRAF6 axis

Nacksung Kim1, Yuho Kadono2, Masamichi Takami3, Junwon Lee1, Seoung-Hoon Lee2, Fumihiko Okada2, Jung Ha Kim1, Takashi Kobayashi2, Paul R. Odgren4, Hiroyasu Nakano5, Wen-Chen Yeh6, Sun-Kyeong Lee7, Joseph A. Lorenzo7, and Yongwon Choi2

1 Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
2 Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Department of Biochemistry, School of Dentistry, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan
4 Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655
5 Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
6 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
7 Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030

CORRESPONDENCE Nacksung Kim: nacksung{at}jnu.ac.kr OR Yongwon Choi: ychoi3{at}mail.med.upenn.edu

Osteoclasts are derived from myeloid lineage cells, and their differentiation is supported by various osteotropic factors, including the tumor necrosis factor (TNF) family member TNF-related activation-induced cytokine (TRANCE). Genetic deletion of TRANCE or its receptor, receptor activator of nuclear factor {kappa}B (RANK), results in severely osteopetrotic mice with no osteoclasts in their bones. TNF receptor-associated factor (TRAF) 6 is a key signaling adaptor for RANK, and its deficiency leads to similar osteopetrosis. Hence, the current paradigm holds that TRANCE–RANK interaction and subsequent signaling via TRAF6 are essential for the generation of functional osteoclasts. Surprisingly, we show that hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can become osteoclasts in vitro when they are stimulated with TNF-{alpha} in the presence of cofactors such as TGF-ß. We provide direct evidence against the current paradigm that the TRANCE–RANK–TRAF6 pathway is essential for osteoclast differentiation and suggest the potential existence of alternative routes for osteoclast differentiation.

N. Kim, Y. Kadono, and M. Takami contributed equally to this work.


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