Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion.
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.
Abe
Masahiro
M
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
Hiura
Kenji
K
Wilde
Javier
J
Shioyasono
Atsushi
A
Moriyama
Keiji
K
Hashimoto
Toshihiro
T
Kido
Shinsuke
S
Oshima
Takashi
T
Shibata
Hironobu
H
Ozaki
Shuji
S
Inoue
Daisuke
D
Matsumoto
Toshio
T
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
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