Bone destruction in multiple myeloma.

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. MM cells enhance bone resorption by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the bone marrow. Macrophage inflammatory protein (MIP)-1alpha and (MIP)-1beta are secreted by MM cells, and play a major role in the enhancement of bone resorption by MM cells. Furthermore, the growth and survival of MM cells are enhanced by contact with osteoclasts (OCs) suggesting the presence of a vicious cycle between OCs and MM cells. OCs also enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from OCs and VEGF from MM cells. The angiogenic effect may further facilitate the vicious cycle between bone destruction and MM cell expansion. In addition, MM cells secrete soluble factor(s) to suppress bone formation. Secreted Frizzled-related protein (sFRP)-2, an inhibitor of Wingless type (Wnt) binding to Frizzled, is produced by most MM cells, and immunodepletion of sFRP-2 abrogates the inhibition of bone formation. Thus, MM cells enhance bone resorption and suppress bone formation to cause destructive bone lesions. Further elucidation of the mechanism of bone destruction by MM may lead to a novel therapeutic approach to prevent bone destruction and tumor growth.