The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis.
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.
Colucci
Silvia
S
Department of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11, Bari 70124, Italy.
Brunetti
Giacomina
G
Cantatore
Francesco Paolo
FP
Oranger
Angela
A
Mori
Giorgio
G
Pignataro
Paolo
P
Tamma
Roberto
R
Grassi
Felice Roberto
FR
Zallone
Alberta
A
Grano
Maria
M
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
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