title: The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis.
abstract: The number and activity of osteoclasts (OCs) are critical for maintaining normal bone turnover. The number is determined by the rates of cell differentiation and death. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis by interacting with its death receptors, (DR4, DR5). However, its activity can be modulated by two decoy receptors, (DcR1 and DcR2). In this paper we show that TRAIL treatment causes reduced OC viability as well as an increased apoptotic OC number. Loss of nuclei integrity and derangement of the actin microfilament were also induced by TRAIL in OCs. Moreover, we demonstrated the expression of all TRAIL receptors in both precursors and differentiated OCs, and the upregulation of DR5 during OC differentiation. Interestingly, DcR2 was upregulated in the early stage of osteoclastogenesis and downregulated at the end of the differentiation process. We showed that DR5, upregulated by TRAIL, could be the mediator of TRAIL-induced OC apoptosis, since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL. Furthermore, the intracellular pathway induced by TRAIL in OCs involves caspase-8 and Bid activation. In conclusion, our data highlight an important role for the TRAIL/TRAIL receptor system in the regulation of OC apoptosis.
authors.affiliation: Department of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11, Bari 70124, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Cantatore
authors.forename: Angela
authors.initials: A
authors.lastname: Oranger
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mori
authors.forename: Paolo
authors.initials: P
authors.lastname: Pignataro
authors.forename: Roberto
authors.initials: R
authors.lastname: Tamma
authors.forename: Felice Roberto
authors.initials: FR
authors.lastname: Grassi
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004789:Enzyme Activation; D058851:GPI-Linked Proteins; D006801:Humans; D010010:Osteoclasts / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000502:physiology; D015854:Up-Regulation
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D058851:GPI-Linked Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D053181:Caspase 8