Multiple Myeloma Disrupts the TRANCE/Osteoprotegerin Cytokine Axis to Trigger Bone Destruction and Promote Tumor Progression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 20; pp. 11581 - 11586
• Main Authors: Pearse, Roger N., Sordillo, Emilia M., Yaccoby, Shmuel, Wong, Brian R., Liau, Deng F., Colman, Neville, Michaeli, Joseph, Epstein, Joshua, Choi, Yongwon
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.09.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Acid Phosphatase - metabolism; Animals; Antibodies; Biological Sciences; Bone marrow; Bones; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell lines; Cells; Coculture techniques; Cytokines; Disease Progression; Genetics; Glycoproteins - antagonists & inhibitors; Glycoproteins - genetics; Glycoproteins - pharmacology; Heterologous transplantation; Hodgkin Disease - pathology; Humans; Isoenzymes - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, SCID; Multiple myeloma; Osteoprotegerin; Paraproteinemias - pathology; Plasma cells; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Tumor Necrosis Factor; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Stromal cells; Studies; Tartrate-Resistant Acid Phosphatase; Time Factors; TRANCE protein; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.201394498

Bone destruction, caused by aberrant production and activation of osteoclasts, 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 decrease in its decoy receptor, osteoprotegerin (OPG). Immunohistochemistry and in situ hybridization studies of bone marrow specimens indicate that in vivo, deregulation of the TRANCE-OPG cytokine axis occurs in myeloma, but not in the limited plasma cell disorder monoclonal gammopathy of unknown significance or in nonmyeloma hematologic malignancies. In coculture, myeloma cell lines stimulate expression of TRANCE and inhibit expression of OPG by stromal cells. Osteoclastogenesis, the functional consequence of increased TRANCE expression, is counteracted by addition of a recombinant TRANCE inhibitor, 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 prevents myeloma-induced bone destruction and interferes with myeloma progression. Our data identify TRANCE and OPG as key cytokines whose deregulation promotes bone destruction and supports myeloma growth.