title: The Proteasome Inhibitor Bortezomib Maintains Osteocyte Viability in Multiple Myeloma Patients by Reducing Both Apoptosis and Autophagy: A New Function for Proteasome Inhibitors.
abstract: Multiple myeloma (MM) is characterized by severely imbalanced bone remodeling. In this study, we investigated the potential effect of proteasome inhibitors (PIs), a class of drugs known to stimulate bone formation, on the mechanisms involved in osteocyte death induced by MM cells. First, we performed a histological analysis of osteocyte viability on bone biopsies on a cohort of 37 MM patients with symptomatic disease. A significantly higher number of viable osteocytes was detected in patients treated with a bortezomib (BOR)-based regimen compared with those treated without BOR. Interestingly, both osteocyte autophagy and apoptosis were affected in vivo by BOR treatment. Thereafter, we checked the in vitro effect of BOR to understand the mechanisms whereby BOR maintains osteocyte viability in bone from MM patients. We found that osteocyte and preosteocyte autophagic death was triggered during coculturing with MM cells. Our evaluation was conducted by analyzing either autophagy markers microtubule-associated protein light chain 3 beta (LC3B) and SQSTM1/sequestome 1 (p62) levels, or the cell ultrastructure by transmission electron microscopy. PIs were found to increase the basal levels of LC3 expression in the osteocytes while blunting the myeloma-induced osteocyte death. PIs also reduced the autophagic death of osteocytes induced by high-dose dexamethasone (DEX) and potentiated the anabolic effect of PTH(1-34). Our data identify osteocyte autophagy as a new potential target in MM bone disease and support the use of PIs to maintain osteocyte viability and improve bone integrity in MM patients.
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Toscani
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Palumbo
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology Unit, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Dalla Palma
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Ferretti
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bolzoni
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchica
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sena
authors.affiliation: Pathology, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Martella
authors.affiliation: Pathology, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mancini
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ferri
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Costa
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology Unit, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Accardi
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Craviotto
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology Unit, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology Unit, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology*
chemical_list: D061988:Proteasome Inhibitors; D000069286:Bortezomib
keywords: AUTOPHAGY; CANCER-INDUCED BONE DISEASE; MULTIPLE MYELOMA; OSTEOCYTES; PROTEASOME INHIBITORS