多発性骨髄腫に伴う骨病変の発症機序とその治療

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and formation of devastating lytic bone lesions. In these lesions MM cells reside in the proximity of stromal cells and osteoclasts (OCs). We have found that C-C chemokines, macrophage inflammatory protein (MIP)-1α and MIP-1β, secreted from most of MM cells potently enhance OC formation and activation. These effects are mostly abrogated by neutralizing antibodies against MIP-1α and MIP-1β in combination, suggesting critical roles for these chemokines in the development of lytic bone lesions. These chemokines induce expression of RANK ligand, a key molecule of osteoclastogenesis, by marrow stromal cells. Furthermore, OC formation and activation induced by MM cells as well as MIP-1α and MIP-1β are almost completely blocked by a surplus of osteoprotegerin, a soluble inhibitor for RANK ligand. These results demonstrate that the osteoytic effects of MM cells are mediated by MIP-1 in a RANK ligand-dependent manner. Interestingly, OCs generated from peripheral blood mononuclear cells enhance survival and growth of MM cells in vitro. The OC effects are only partially inhibited by anti-IL-6 but strongly by contact inhibition between MM cells and OCs, suggesting involvement of IL-6-independent contact-mediated mechanism(s). Taken together, a cellular interplay between MM cells and OCs stimulates their growth and activity, thereby forming a vicious cycle that leads to extensive bone destruction and MM expansion. Bisphosphonates are a potent anti-bone resorptive agent and show effective palliation of bone pain and improvement of quality of life in patients with an advanced disease. Clinical trials with newly developed anti-resorptive agents are ongoing. However, their role in prophylaxis, long-term efficacy and optimal therapeutic schedules remain to be established from well-designed clinical trials.