Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression

Bone destruction, caused by aberrant production and activation of osteoclas ts, is a prominent feature of multiple myeloma. We demonstrate that myeloma stimulates osteoclastogenesis by triggering a coordinated increase in the tumor necrosis factor-related activation-induced cytokine (TRANCE) and decr ease in its decoy receptor, osteoprotegerin (OPG). Immunohistochemistry and in situ hybridization studies of bone marrow specimens indicate that in vi vo, deregulation of the TRANCE-OPG cytokine axis occurs in myeloma, but not in the limited plasma cell disorder monoclonal gammopathy of unknown signi ficance or in nonmyeloma hematologic malignancies. In coculture, myeloma ce ll lines stimulate expression of TRANCE and inhibit expression of OPG by st romal cells. Osteoclastogenesis, the functional consequence of increased TR ANCE expression, is counteracted by addition of a recombinant TRANCE inhibi tor, RANK-Fc, to marrow/myeloma cocultures. Myeloma-stroma interaction also has been postulated to support progression of the malignant clone. In the SCID-hu murine model of human myeloma, administration of RANK-Fc both preve nts myeloma-induced bone destruction and interferes with myeloma progressio n. Our data identify TRANCE and OPG as key cytokines whose deregulation pro motes bone destruction and supports myeloma growth.