Role of TRAF6 in TRAIL-induced osteoclastogenesis
Date Issued
2008
Date
2008
Author(s)
Lee, Be-Han
Abstract
Osteoclasts are multinucleated cells (MNCs) that are differentiated from macrophage/ monocyte lineage of hematopoietic precursors. Receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, plays a key role in osteoclast differentiation. RANKL binds to its receptor RANK, which recruits TNF receptor associated factor 6 (TRAF6) and activates NF-κB, Akt, and mitogen-activated protein kinase (MAPK) pathways finally leading to osteoclast-specific genes expression. In addition to RANKL, more and more studies indicated that some TNF family members including TNF-α, FasL and LIGHT are involved in differentiation and function of osteoclasts. These studies suggested that some TNF-family cytokines may regulate osteoclast differentiation. In addition to induction of apoptosis, TNF-related apoptosis inducing ligand (TRAIL) exerts different function that includes survival, proliferation and maturation. Our previous studies have demonstrated that TRAIL can induce osteoclasts differentiation from murine monocytic cell line, RAW 264.7 and human peripheral mononuclear cells (PBMCs), and this signaling pathway is distinct from apoptosis signaling. TRAIL could activate NF-κB and MAPKs, which are important for RANKL-induced osteoclastogenesis. However, the signaling pathway that leads to downstream molecules activation and resulting in osteoclastogenesis remains unclear. TRAF6 is critical in RANKL-induced osteoclastogenesis. Cells from TRAF6-deficient mice can not differentiate into osteoclasts in the presence of RANKL. Therefore, we hypothesize that TRAIL stimulation activates MAPKs and NF-κB pathways to induce osteoclastogenesis through adaptor molecule, TRAF6. To determine whether TRAF6 is involved in TRAIL-induced osteoclastogenesis, we used TRAF6 siRNA to inhibit TRAF6 expression. After knockdown TRAF6 expression by transfection of TRAF6 siRNA, we found that similar to RANKL, osteoclast formation was reduced after TRAIL stimulation. We further investigated whether suppression of TRAF6 expression might affect TRAIL-induced NF-κB and MAPKs activation. Our results demonstrated that knockdown TRAF6 expression reduced TRAIL-induced MAPK activation. In conclusion, TRAIL induces osteoclast differentiation via activation of MAPK which is dependent on TRAF6. Our results provide a novel mechanism that TRAIL can transduce a non-apoptotic signal mediated by TRAF6 to induce osteoclast formation.
Subjects
osteoclastogenesis
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