Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells.
Myeloma cells grow only in the bone marrow closely associated with bone,suggesting that this microenvironment provides critical signals for their growth and survival. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family, which binds to the ligand for receptor activator of nuclear factor kappa B and inhibits bone resorption. However, it is unclear whether OPG can also bind to other TNF family members, such as TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L), and, by inhibiting their activity, function as a survival factor for myeloma cells. In the present study MG63 osteoblast-like cells and primary bone marrow stromal cells were both shown to produce OPG, whereas human myeloma cells did not produce OPG but down-regulated release of OPG from MG63 cells. TRAIL/Apo2L induced apoptosis in myeloma cells, and this could be prevented with the addition of recombinant OPG. Medium conditioned by MG63 cells was also shown to inhibit TRAIL/Apo2L-induced apoptosis, an effect that was reversed by the addition of soluble receptor activator of nuclear factor kappa B ligand. Medium conditioned by cocultures of MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2L-induced apoptosis, reflecting the decreased concentrations of OPG in cocultures of myeloma cells with bone cells. These observations suggest that OPG may function as a paracrine survival factor in the bone marrow microenvironment in multiple myeloma.
Shipman
Claire M
CM
Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Center, Oxford OX3 7LD, United Kingdom. claire.shipman@ndos.ox.ac.uk
Croucher
Peter I
PI
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha