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TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation.

Yen ML, Hsu PN, Liao HJ, Lee BH, Tsai HF - PLoS ONE (2012)

Bottom Line: In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation.Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway.This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of General Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

ABSTRACT
Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.

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A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation.Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6, at least in part through the E3 ubiquitin ligase activity of the TRAF6 RING finger domain via a distinct signaling pathway. In osteoclast precursors, TRAIL is not able to induce sufficient amount of signals to activate the downstream apoptosis signaling to induce apoptosis; instead, TRAIL induces signaling to activate TRAF6 after receptor engagement. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. These signals include activation of NF-κB by a process of ubiquitination in which TRAF6 functions as an E3 ligase [36] and recruitment of the TAB1-TAB2-TAK1 complex, which lead to the osteoclast-specific event, that is, autoamplification of NFATc1, the master transcription factor for osteoclast differentiation [29], [30], [31].
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pone-0038048-g006: A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation.Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6, at least in part through the E3 ubiquitin ligase activity of the TRAF6 RING finger domain via a distinct signaling pathway. In osteoclast precursors, TRAIL is not able to induce sufficient amount of signals to activate the downstream apoptosis signaling to induce apoptosis; instead, TRAIL induces signaling to activate TRAF6 after receptor engagement. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. These signals include activation of NF-κB by a process of ubiquitination in which TRAF6 functions as an E3 ligase [36] and recruitment of the TAB1-TAB2-TAK1 complex, which lead to the osteoclast-specific event, that is, autoamplification of NFATc1, the master transcription factor for osteoclast differentiation [29], [30], [31].

Mentions: In this study, we demonstrated that TRAIL induced monocyte/macrophage lineage precursor cells to differentiate into osteoclast-like cells, and TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. Osteoclast formation from mononuclear phagocyte precursors involves interactions between TNF ligand superfamily members and their receptors [2], [3], [4], [6], [7]. However, the signaling pathways and whether TRAF6-dependent signaling is essential for TRAIL-induced osteoclast differentiation is still not clear. Our data is the first to demonstrate TRAF6 is essential for TRAIL induces osteoclast differentiation and bone resorption activity. A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation is shown in Figure 6. Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6 via a distinct signaling pathway. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling. This will provide new insights into the molecular mechanism which may implicate osteoimmunology in the immune response associated with bone absorption.


TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation.

Yen ML, Hsu PN, Liao HJ, Lee BH, Tsai HF - PLoS ONE (2012)

A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation.Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6, at least in part through the E3 ubiquitin ligase activity of the TRAF6 RING finger domain via a distinct signaling pathway. In osteoclast precursors, TRAIL is not able to induce sufficient amount of signals to activate the downstream apoptosis signaling to induce apoptosis; instead, TRAIL induces signaling to activate TRAF6 after receptor engagement. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. These signals include activation of NF-κB by a process of ubiquitination in which TRAF6 functions as an E3 ligase [36] and recruitment of the TAB1-TAB2-TAK1 complex, which lead to the osteoclast-specific event, that is, autoamplification of NFATc1, the master transcription factor for osteoclast differentiation [29], [30], [31].
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3375273&req=5

pone-0038048-g006: A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation.Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6, at least in part through the E3 ubiquitin ligase activity of the TRAF6 RING finger domain via a distinct signaling pathway. In osteoclast precursors, TRAIL is not able to induce sufficient amount of signals to activate the downstream apoptosis signaling to induce apoptosis; instead, TRAIL induces signaling to activate TRAF6 after receptor engagement. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. These signals include activation of NF-κB by a process of ubiquitination in which TRAF6 functions as an E3 ligase [36] and recruitment of the TAB1-TAB2-TAK1 complex, which lead to the osteoclast-specific event, that is, autoamplification of NFATc1, the master transcription factor for osteoclast differentiation [29], [30], [31].
Mentions: In this study, we demonstrated that TRAIL induced monocyte/macrophage lineage precursor cells to differentiate into osteoclast-like cells, and TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. Osteoclast formation from mononuclear phagocyte precursors involves interactions between TNF ligand superfamily members and their receptors [2], [3], [4], [6], [7]. However, the signaling pathways and whether TRAF6-dependent signaling is essential for TRAIL-induced osteoclast differentiation is still not clear. Our data is the first to demonstrate TRAF6 is essential for TRAIL induces osteoclast differentiation and bone resorption activity. A model for TRAIL-induced activation of the TRAF6 associated signaling pathway in osteolcast differentiation is shown in Figure 6. Upon receptor engagement, in addition to transduce apoptosis signaling pathway, TRAIL induces activation of TRAF6 via a distinct signaling pathway. TRAF6 is the key molecule linking cytoplasmic signaling to the nuclear transcriptional program in osteoclast differentiation and bone resorption. TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling. This will provide new insights into the molecular mechanism which may implicate osteoimmunology in the immune response associated with bone absorption.

Bottom Line: In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation.Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway.This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of General Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

ABSTRACT
Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.

Show MeSH
Related in: MedlinePlus