title: Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation.
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.
authors.affiliation: Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Palermo, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Manno
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Palermo, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Raccosta
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Taverna
authors.affiliation: Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bellavia
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Flores
authors.initials: F
authors.lastname: Naselli
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Fontana
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Odessa
authors.initials: O
authors.lastname: Schillaci
authors.affiliation: Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giardino
authors.affiliation: Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Fini
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Divisione di Ematologia A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: De Leo
authors.affiliation: Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.|Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giavaresi
authors.affiliation: Section of Biology and Genetics, Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.|Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council of Italy, Palermo, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D059016:Tumor Microenvironment
keywords: exosomes; multiple myeloma; osteoclasts; tumor microenvironment