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.
Highlights
Osteoclasts are multinucleated cells, derived from precursors of monocyte/macrophage lineages
This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and tumor necrosis factor (TNF) other than RANK ligand (RANKL) may modify receptor activator of nuclear factor-kB (RANK) signaling by interaction with TRAF6-associated signaling
We demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) induced monocyte/macrophage lineage precursor cells to differentiate into osteoclast-like cells, and TRAIL induces osteoclastic differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6) dependent signaling pathway
Summary
Osteoclasts are multinucleated cells, derived from precursors of monocyte/macrophage lineages. In addition to RANKL, recent studies have demonstrated there are several TNF family molecules which promote osteoclast differentiation, including TNF [11], decoy receptor 3 (DcR3) [12], FasL [13] and TRAIL [14]; indicating that activated T cells and inflammatory response can remodel bone homeostasis via these effector molecules. The mechanism and signaling pathways of TRAIL-induced osteoclast differentiation is still not clear Ligands for these receptors plus unidentified serum or cellpresented factor(s) are necessary for in vitro differentiation, indicating the involvement of signaling pathways possibly via an immune-like tyrosine kinase acceptor molecule. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and TNFs other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling
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