Identification and clinical application of osteoclast-derived growth factors for myeloma

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Multiple myeloma (MM) almost exclusively develops in the bone marrow, suggesting that the bone marrow microenvironment supports MM cell growth and survival. We found that the growth and survival of MM cells are potently enhanced by osteoclasts (Ocs). The effects of OCs were only partially inhibited by an anti-human IL-6 neutralizing antibody despite the increased production of IL-6 by OCs in co-cultures with MM cells. Furthermore, prevention of a cellular contact between MM cells and OCs by membrane filters completely abolished the OC effect. Therefore, OCs may enhance MM cell growth largely through a close cell-cell interaction by elaborating unknown factor(s) other than IL-6. Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in patients with MM, which has drawn considerable attention as a potential therapeutic target. We also found that OCs constitutively secrete high levels of an angiogenic noncollagenous matrix protein, osteopontin (OPN), which is known to cooperatively act with VEGF in angiogenesis. Conditioned media (CM) from OCs enhanced vascular tubule formation as potently as those from MM cells. Interestingly, CM from co-cultures of both cells further enhanced it, suggesting cooperative interactions between OCs and MM cells in angiogenesis. Antibodies against OPN or VEGF each alone partially and both in combination almost completely abrogated vascular tubule formation enhanced by CM from the co-cultures. Therefore, OCs enhance angiogenesis in concert with MM cells, which is largely mediated by cooperative actions of OPN and VEGF derived from OCs and MM cells, respectively. Collectively, OCs may enhance MM progression not only directly but also through enhanced angiogenesis, thereby forming a vicious cycle between bone destruction and MM expansion.