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Blood, 15 October 2009, Vol. 114, No. 16, pp. 3413-3421. Prepublished online as a Blood First Edition Paper on August 6, 2009; DOI 10.1182/blood-2009-03-211920. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-03-211920v1 114/16/3413    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Kukreja, A. Articles by Dhodapkar, M. V. PubMed PubMed Citation Articles by Kukreja, A. Articles by Dhodapkar, M. V. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease Anjli Kukreja1, Soroosh Radfar1, Ben-Hua Sun2, Karl Insogna2, and Madhav V. Dhodapkar1,3 Sections of 1 Hematology, 2 Endocrinology, and 3 Immunobiology, Yale University, New Haven, CT Lytic bone disease in myeloma is characterized by an increase in multinucleate osteoclasts in close proximity to tumor cells. However, the nature of osteoclast precursors and the mechanisms underlying multinuclearity are less understood. Here we show that culture of myeloma cell lines as well as primary myeloma cells with human dendritic cells (DCs) but not monocytes or macrophages leads to spontaneous cell-cell fusion, which then leads to the facile formation of multinucleate bone-resorbing giant cells. Osteoclastogenesis is cell contact dependent, leading to up-regulation of thrombospondin-1 (TSP-1) in DCs. Disruption of CD47–TSP-1 interaction by TSP-1–blocking antibodies or down-regulation of CD47 on tumor cells by RNA interference abrogates tumor-induced osteoclast formation. Blockade of CD47–TSP-1 interactions also inhibits receptor activator for nuclear factor B ligand- and macrophage colony-stimulating factor–induced formation of osteoclasts from human monocytes. Further, TSP-1 blockade attenuates hypercalcemia induced by parathyroid hormone in vivo. These data point to a role for CD47–TSP-1 interactions in regulating cell-fusion events involved in human osteoclast formation. They also suggest that DCs, known to be enriched in myeloma tumors, may be direct precursors for tumor-associated osteoclasts. Disruption of CD47–TSP-1 interactions or preventing the recruitment of DCs to tumors may provide novel approaches to therapy of myeloma bone disease and osteoporosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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