T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction.
The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell-depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.
Department of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11, 70124 Bari, Italy.
Silvia
S
Colucci
Giacomina
G
Brunetti
Rita
R
Rizzi
Antonia
A
Zonno
Giorgio
G
Mori
Graziana
G
Colaianni
Davide
D
Del Prete
Roberta
R
Faccio
Arcangelo
A
Liso
Silvana
S
Capalbo
Vincenzo
V
Liso
Alberta
A
Zallone
Maria
M
Grano
D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D001847:Bone Diseases / Q000473:pathology*; D016022:Case-Control Studies; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D053244:Osteoprotegerin; D011485:Protein Binding / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha