title: Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion.
abstract: Multiple myeloma (MM) expands in the bone marrow and causes devastating bone destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting a close interaction between MM cells and osteoclasts (OCs). Here, we show that peripheral blood mononuclear cell-derived OCs enhanced growth and survival of primary MM cells as well as MM cell lines more potently than stromal cells, and that OCs protected MM cells from apoptosis induced by serum depletion or doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6 and OPN in combination enhanced MM cell growth and survival. However, the effects of OCs on MM cell growth and survival were only partially suppressed by a simultaneous addition of anti-IL-6 and anti-OPN antibodies and were completely abrogated by inhibition of cellular contact between MM cells and OCs. These results demonstrate that OCs enhance MM cell growth and survival through a cell-cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It is suggested that interactions of MM cells with OCs augment MM growth and survival and, thereby, form a vicious cycle, leading to extensive bone destruction and MM cell expansion.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. masabe@clin.med.tokushima-u.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.forename: Kenji
authors.initials: K
authors.lastname: Hiura
authors.forename: Javier
authors.initials: J
authors.lastname: Wilde
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shioyasono
authors.forename: Keiji
authors.initials: K
authors.lastname: Moriyama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kido
authors.forename: Takashi
authors.initials: T
authors.lastname: Oshima
authors.forename: Hironobu
authors.initials: H
authors.lastname: Shibata
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Inoue
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D053495:Osteopontin; D011817:Rabbits; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology
chemical_list: D000906:Antibodies; D016895:Culture Media, Serum-Free; D004164:Diphosphonates; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D015850:Interleukin-6; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; D004317:Doxorubicin