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KOS 2007: Pathophysiology of Myeloma Bone Disease
By Peter Croucher, MD
Peter Croucher, MD
Section of Musculoskeletal Science
University of Sheffield Medical School
Sheffield, UK

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AUTHORS: P.I. Croucher,1 D. Heath,1 A. Chantry,1 M. Lawson,1 C. Buckle,1 K. Vanderkerken2
1Section of Musculoskeletal Science, University of Sheffield Medical School, Sheffield, UK; 2Department Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium

By Lynne Lederman, PhD

The majority (69%) of fractures in patients with myeloma are pathologic; the rest are osteoporotic. Interaction of myeloma cells with both osteoclasts and osteoblasts uncouples bone formation and resorption. RANK ligand (RANKL), the receptor activator of NF-κB and its decoy receptor osteoprotegerin (OPG) are abnormally expressed in myeloma. Increased RANKL expression may directly drive osteoclast formation. The last 4 to 5 years has seen progress in the use of animal models to study the pathophysiology of myeloma bone disease. The 5T2MM murine model develops bone disease, whereas the 5T33MM does not and serves as a control. Although OPG blocks the development of bone disease in 5T2MM, it can bind to other ligands, e.g., TRAIL. OPG peptides, mimetics, and lentiviral constructs can block RANKL osteoclast formation and inhibit bone disease without affecting other ligands, and most, but not all reduce tumor burden. RANKL plays a critical role in bone disease but other factors, which may function through RANKL, are also involved, such as macrophage inflammatory protein (MIP)-1α, and stromal-derived factory (SDF)-1α. It is possible that different molecular subtypes of myeloma may use different signaling pathways to drive bone destruction. Wnt signaling is important in bone formation, and dickkopf-1 (DKK1), an inhibitor of Wnt signaling is produced by some myeloma cells. Anti-DKK1 antibodies prevent myeloma bone disease in the SCID-rabbit model. Other molecules, including IL-3, IL-7, SFRP2, HGF, and VLA-4 have also been implicated in myeloma bone disease. Currently the temporal and spatial regulation of bone formation and destruction is unclear, as is the relationship of molecular subtypes to bone disease.

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