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 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.
Kim
Nacksung
N
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Korea. nacksung@jnu.ac.kr
Kadono
Yuho
Y
Takami
Masamichi
M
Lee
Junwon
J
Lee
Seoung-Hoon
SH
Okada
Fumihiko
F
Kim
Jung Ha
JH
Kobayashi
Takashi
T
Odgren
Paul R
PR
Nakano
Hiroyasu
H
Yeh
Wen-Chen
WC
Lee
Sun-Kyeong
SK
Lorenzo
Joseph A
JA
Choi
Yongwon
Y
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D017931:DNA Primers; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006652:Histological Techniques; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002352:Carrier Proteins; D017931:DNA Primers; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha