// Lavinia Raimondi 1 , Angela De Luca 1 , Nicola Amodio 2 , Mauro Manno 3 , Samuele Raccosta 3 , Simona Taverna 4 , Daniele Bellavia 1 , Flores Naselli 4 , Simona Fontana 4 , Odessa Schillaci 4 , Roberto Giardino 5 , Milena Fini 6 , Pierfrancesco Tassone 2 , Alessandra Santoro 7 , Giacomo De Leo 4 , Gianluca Giavaresi 1,6 and Riccardo Alessandro 4,8 1 Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy 2 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy 3 Institute of Biophysics, National Research Council of Italy, Palermo, Italy 4 Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy 5 Rizzoli Orthopedic Institute, Bologna, Italy 6 Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Bologna, Italy 7 Divisione di Ematologia A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo 8 Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council of Italy, Palermo, Italy Correspondence to: Riccardo Alessandro, email: // Keywords : exosomes, multiple myeloma, osteoclasts, tumor microenvironment Received : February 02, 2015 Accepted : March 26, 2015 Published : April 12, 2015 Abstract Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient’s sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes.
Giavaresi, G., Fini, M., Fontana, S., Bellavia, D., Manno, M., Tassone, P., … Schillaci, O. (2015). Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation. Oncotarget, 6(15). https://doi.org/10.18632/oncotarget.3830