Abstract
Receptor activator of nuclear factor-kappaB 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. 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. 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.
Highlights
Receptor activator of nuclear factor-nB ligand (RANKL) is a key mediator of osteoclastogenesis
The following reagents were purchased from the indicated manufacturers: recombinant human soluble RANKL from Pepro Tech (London, United Kingdom); rhM-CSF, rhVEGF, mouse monoclonal antibodies against human RANKL (TRANCE), IL-1h, IL-6, and CD68 from R&D Systems (Minneapolis, MN); anti-human RANKL, RANK, osteoprotegerin, vascular endothelial cell growth factor (VEGF), parathyroid hormone – related protein monoclonal antibody from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); antihuman CD20 monoclonal antibody from Becton Dickinson (Mountain View, CA); antitartrate-resistant acid phosphatase (TRAP) antibody from Novocastra (Newcastle-upon-tyne, United Kingdom); antihuman macrophage inflammatory protein-1a monoclonal antibody from Chemicon International, Inc. (Temecula, CA)
To clarify whether lymphoma cells aberrantly express RANKL to cause bone destruction, we first immunohistochemically examined RANKL expression in bone tissue samples obtained from patients with primary bone lymphoma and nodal lymphoma infiltrating to the bone marrow without bone destruction
Summary
Receptor activator of nuclear factor-nB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. 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. Certain types of B-lymphoid neoplasms, such as lymphoma of bone origin and multiple myeloma, exclusively develop and expand in the skeleton These tumors cause lytic bone lesions, which lead to the debilitating clinical symptoms including intractable bone pain and disabling fractures. We show that a portion of B-lymphoid tumor cell lines as well as primary B-lymphoid tumor cells of bone origin aberrantly express RANKL and VEGF, and directly induce osteoclastogenesis from osteoclast progenitors via cell-to-cell contact. The present results show that a close interaction between B-lymphoid tumor cells and osteoclasts augments mutual growth and activity
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