interaction human multiple myeloma bone disease: the role of the OPG/Trail T cells support osteoclastogenesis in an in vitro model derived from

ABSTRACT 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 MM patients, we showed that T cells support the formation of OCs with longer survival. Differently in T cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL) were necessary to the formation of OCs, not exhibiting however 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