title: TNF-related apoptosis-inducing ligand (TRAIL) blocks osteoclastic differentiation induced by RANKL plus M-CSF.
abstract: The role of the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor kappa B ligand (RANKL) in promoting the differentiation of osteoclasts has been extensively characterized. In this study, we have investigated the effect of TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, in osteoclastogenesis, by using human peripheral blood mononuclear cells and the RAW264.7 murine monocytic cell line. Both cell models differentiate into osteoclast-like cells in presence of RANKL plus macrophage-colony-stimulating factor (M-CSF), as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Unexpectedly, when added in culture in combination with RANKL plus M-CSF, TRAIL inhibited osteoclastic differentiation in both cell models. To investigate the molecular mechanism underlining such inhibitory activity, we analyzed the effect of TRAIL on the mitogen-activated protein kinases (MAPKs) pathways, which play a key role in osteoclastogenesis. Treatment with RANKL plus M-CSF activated both the ERK1/2 and p38/MAPK pathways, which are essential for proliferation and differentiation of preosteoclasts, respectively. Of note, the addition of TRAIL to RANKL plus M-CSF did not affect ERK1/2 but it profoundly inhibited p38/MAPK phosphorylation. Thus, our data demonstrate that TRAIL blocks osteoclastic differentiation and suggest that inhibition of the p38/MAPK pathway by TRAIL likely plays an important role in this process.
authors.affiliation: Department of Normal Human Morphology, University of Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nicolin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.forename: Claudio
authors.initials: C
authors.lastname: Celeghini
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D001862:Bone Resorption; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010766:Phosphorylation; D053245:RANK Ligand; D012313:RNA / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505686:TNFRSF11A protein, human; C505653:TNFSF10 protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505654:Tnfsf10 protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases