Human Myeloma Cells Ligand and Can Function as a Paracrine Survival Factor for Necrosis Factor-related Apoptosis-inducing Ligand/Apo2 Osteoprotegerin Is a Soluble Decoy Receptor for Tumor

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 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 B ligand. Medium conditioned by cocultures of MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2Linduced 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.