Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis

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 nucle...

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Bibliographic Details
Published in:The Journal of experimental medicine 2005-09, Vol.202 (5), p.589-595
Main Authors: Kim, Nacksung, Kadono, Yuho, Takami, Masamichi, Lee, Junwon, Lee, Seoung-Hoon, Okada, Fumihiko, Kim, Jung Ha, Kobayashi, Takashi, Odgren, Paul R, Nakano, Hiroyasu, Yeh, Wen-Chen, Lee, Sun-Kyeong, Lorenzo, Joseph A, Choi, Yongwon
Format: Article
Language:English
Subjects:
Animals
Brief Definitive Report
Carrier Proteins - genetics
Cell Differentiation - drug effects
DNA Primers
Gene Deletion
Hematopoietic Stem Cells - drug effects
Histological Techniques
Lymphotoxin-alpha - pharmacology
Male
Membrane Glycoproteins - deficiency
Membrane Glycoproteins - genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoclasts - cytology
Osteoclasts - metabolism
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - physiology
TNF Receptor-Associated Factor 6 - deficiency
TNF Receptor-Associated Factor 6 - genetics
Tumor Necrosis Factor-alpha - pharmacology
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Summary: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 kappaB (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-beta. 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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20050978