Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease

• Published in: Blood Vol. 114; no. 16; pp. 3413 - 3421
• Main Authors: Kukreja, Anjli, Radfar, Soroosh, Sun, Ben-Hua, Insogna, Karl, Dhodapkar, Madhav V.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-10-2009; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Antibodies, Monoclonal - pharmacology; Biological and medical sciences; CD47 Antigen - metabolism; Cell Fusion; Cell Line, Tumor; Dendritic Cells - metabolism; Hematologic and hematopoietic diseases; Humans; Immunobiology; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; NF-kappa B - metabolism; Osteoclasts - metabolism; Osteolysis - drug therapy; Osteolysis - metabolism; RNA Interference; Thrombospondin 1 - metabolism; Human; Immunopathology; Dendritic cell; Hematology; Diseases of the osteoarticular system; B cell neoplasm; Malignant hemopathy; Lymphoid neoplasm; Cell fusion; Myeloma; Thrombospondin 1; Immunoglobulinopathy; Antigen presenting cell; Integrin associated protein; Lymphoproliferative syndrome; Antiangiogenic agent; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-03-211920

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 κB 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.