| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Toshio The University of Tokushima, Medical School, Professor, 医学研究科, 教授 (20157374)
INOUE Daisuke The University of Tokushima, Medical School, Assistant Professor, 医学研究科, 助手 (60314853)
OZAKI Shuji The University of Tokushima, Univ.Hospital, Lecturer, 医学部附属病院, 講師 (90314872)
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| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
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
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