IGF2 derived from SH-SY5Y neuroblastoma cells induces the osteoclastogenesis of human monocytic precursors |
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Authors: | Avnet Sofia Salerno Manuela Quacquaruccio Gianni Granchi Donatella Giunti Armando Baldini Nicola |
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Institution: | aLaboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, via di Barbiano 1/10, 40136, Bologna, Italy;bDepartment of Orthopaedic Surgery, University of Bologna, via di Barbiano 1/10, 40136, Bologna, Italy |
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Abstract: | The insulin-like growth factors 2 (IGF2) is a peptide hormone that binds to the insulin-like growth factor 1 receptor (IGF1R) and is abundantly stored in bone. IGF1R is deeply involved in the pathogenesis of many cancers that growth within bone and is also involved in osteoclast biology. Among different cell lines representative of osteolytic tumors, we found a very high expression of IGF2 in SH-SY5Y cells derived from neuroblastoma (NB). We previously showed that NB cells induce an osteolytic process through the Osteoprotegerin/RANKL/RANK and the canonical Wnt pathway system. Here, we hypothesized that NB promotes osteoclastogenesis also via IGF2. First, we demonstrated the presence of IGF1R on the osteoclast basolateral membrane, and we observed a cyclic IGF1R activation along with the differentiation process, also when induced by SH-SY5Y. Moreover, we found that IGF2 mRNA expression in SH-SY5Y cells was further increased when co-cultured with mesenchymal stromal cells, suggesting that IGF2 is important for NB interaction with the bone microenvironment. Finally, the treatment of SH-SY5Y cells with an anti-IGF2 siRNA or the addition of anti-IGF1R molecules impaired NB-induced osteoclastogenesis, even though the chemoattraction of monocytes by NB cells was unaffected. Our findings suggest that in IGF2-producing osteolytic tumors IGF1R is a good candidate for targeted therapies in combination with conventional drugs. |
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Keywords: | Abbreviations: NB Neuroblastoma Dkk1 Dickkopf 1 RANK receptor activator of nuclear factor kappaB RANKL receptor activator of nuclear factor kappaB ligand IL-6 interleukine-6 TGFβ transforming growth factor beta FGFs fibroblast growth factors IGFs insulin-like growth factors IGF-1 insulin-like growth factor 1 BMP-2 bone morphogenetic protein 2 TRACP tartrate-resistant acid phosphatase TPA 12-O-tetradecanoylphorbol-13-acetate MSC marrow stromal cells PBMC peripheral blood mononuclear cells IGF1 insulin-like growth factor 1 IGF2 insulin-like growth factor 2 IGF1R insulin-like growth factor receptor type I MMP9 matrix metalloproteinase 9 Ctr control MAb monoclonal antibody NFATc1 Nuclear Factor of Activated T-cell 1 cm conditioned medium IGFBPs IGF binding proteins cm conditioned medium |
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