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Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-B Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis

Authors' Affiliations: Departments of ¹ Medicine and Bioregulatory Sciences, ² Orthodontics, and ³ Human Pathology, University of Tokushima Graduate School of Health Biosciences; ⁴ Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan; and ⁵ Division of Pathology, Hyogo Prefectural Awaji Hospital, Hyogo, Japan

Requests for reprints: Masahiro Abe, Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Health Biosciences, 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: Receptor activator of nuclear factor-B ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms.

Experimental Design and Results: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell–derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells.

Conclusions: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.

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