Multiple myeloma is a B-cell
malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic
bone disease. Myeloma cells express the
receptor activator of nuclear factor kappaB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate expression of the decoy receptor
osteoprotegerin, thereby promoting
bone resorption. Targeting this system in myeloma has clear therapeutic potential. However,
osteoprotegerin also binds
tumor necrosis factor-related apoptosis inducing
ligand (TRAIL) and prevents TRAIL-induced apoptosis of myeloma cells. Whether or not
osteoprotegerin can bind TRAIL and prevent apoptosis in vivo and the relative importance of
osteoprotegerin binding to TRAIL and RANKL are unclear. In the present study, we have investigated the ability of an
osteoprotegerin-like
peptidomimetic (OP3-4), designed to block the RANKL/RANK interaction, to inhibit osteoclastic
bone resorption and TRAIL-induced apoptosis in vitro and myeloma
bone disease in vivo. OP3-4 inhibited osteoclast formation (P < 0.01) and
bone resorption (P < 0.01) in vitro. However, OP3-4 had no effect on TRAIL-induced apoptosis of RPMI 8226 myeloma cells. Treatment of 5T2MM myeloma-bearing mice with OP3-4 decreased osteoclast number and the proportion of bone surface covered by osteoclasts (P < 0.05). Treatment also prevented the
tumor-induced decrease in cancellous bone area and the development of osteolytic lesions (P < 0.05). OP3-4 also reduced
tumor burden when compared with the control (P < 0.05). These data suggest that OP3-4 and the selective inhibition of RANKL, but not TRAIL activity, are effective in preventing myeloma
bone disease and offer a novel therapeutic approach to treating this aspect of myeloma. [
Cancer Res 2007;67(1):202-8].