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Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin

Authors' Affiliations: ¹ Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences; ² Department of Orthodontics, University of Tokushima Graduate School of Dental Sciences; ³ 21st Century Center of Excellence Program of the University of Tokushima; and ⁴ Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan

Requests for reprints: Masahiro Abe, Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. Phone: 81-88-633-7120; Fax: 81-88-633-7121; E-mail: masabe{at}clin.med.tokushima-u.ac.jp.

Purpose: Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in myeloma in parallel with tumor progression. We showed previously that myeloma cells and osteoclasts are mutually stimulated to form a vicious cycle to lead to enhance both osteoclastogenesis and tumor growth. The present study was undertaken to clarify whether myeloma cell-osteoclast interaction enhances angiogenesis and whether there is any mutual stimulation between osteoclastogenesis and angiogenesis.

Experimental Design: Myeloma cells and monocyte-derived osteoclasts were cocultured, and angiogenic activity produced by the cocultures was assessed with in vitro vascular tubule formation assays and human umbilical vascular endothelial cell (HUVEC) migration and survival. Osteoclastogenic activity was determined with rabbit bone cell cultures on dentine slices.

Results: Myeloma cells and osteoclasts constitutively secrete proangiogenic factors, vascular endothelial growth factor (VEGF) and osteopontin, respectively. A cell-to-cell interaction between myeloma cells and osteoclasts potently enhanced vascular tubule formation. Blockade of both VEGF and osteopontin actions almost completely abrogated such vascular tubule formation as well as migration and survival of HUVECs enhanced by conditioned medium from cocultures of myeloma cells and osteoclasts. Furthermore, these factors in combination triggered the production of osteoclastogenic activity by HUVEC.

Conclusions: Osteoclast-derived osteopontin and VEGF from myeloma cells cooperatively enhance angiogenesis and also induce osteoclastogenic activity by vascular endothelial cells. These observations suggest the presence of a close link between myeloma cells, osteoclasts, and vascular endothelial cells to form a vicious cycle between bone destruction, angiogenesis, and myeloma expansion.

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