Roles for MIP-1α and β in the development of osteolytic lesions in multiple myeloma

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Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells -in the bone marrow and formation of devastating lytic bone lesions. Osteoclasts (OCs) fromation and bone resorption are enhanced in vitro by co-cultures with MM cells as well as addition of MM cell-conditioned media, suggesting involvement of MM-derived secreted factors and direct interaction with these cells. We have found that C-C chemokines, macrophage inflammatory protein. (MIP)-1α and β, are secreted from most of MM cells, and potently induce -OC formation _and activation. These effects are mostly abrogated by neutralizing antibodies against MIP-1α and β in combination, suggesting critical roles for these chemokines in the development of lytic bone lesions. Furthermore, secretion levels of MIP-1α and β from MM cells correlate well with the severity of bone resorption, providing a clinical evidence for a causal role of MIP=1a and b. These chemokines induce expression of RANK ligand, a key molecule of osteoclastogenesis, by, marrow stromal cells. Importantly, OC formation and activation by MM cells as well as MIP-1α and β are completely blocked by a surplus of osteoprotegerin, a soluble inhibitor of RANK ligand. These results demonstrate that the osteblytic effects of MM cells are mediated by MIP-1 in RANK-ligand-dependent manner. Moreover, MIP-1 acts on MM cells in an autocrine fashion to stimulate adhesion of MM cells to VCAM-1 by activating VLA-4, a VCAM-1 receptor abundantly expressed on MM cells. Adhesion of MM cells via VLA-4/VCAM-1 enhances the secretion of MIP-1 α, and β from MM cells, which further stimulates osteoclastogenesis. In conclusions, MIP-1α and β are among leading candidates for MM-derived factors that enhance OC differentiation and function, thereby causing extensive bone destruction. Inhibition of production and/or activities of these chemokines as well as RANK ligand may be a rational target of treatment against bone disease in MM