The Proteasome Inhibitor Bortezomib Maintains Osteocyte Viability in Multiple Myeloma Patients by Reducing Both Apoptosis and Autophagy: A New Function for Proteasome Inhibitors

Denise Toscani, Carla Palumbo, Benedetta Dalla Palma, Marzia Ferretti, Marina Bolzoni, Valentina Marchica, Paola Sena, Eugenia Martella, Cristina Mancini, Valentina Ferri, Federica Costa, Fabrizio Accardi, Luisa Craviotto, Franco Aversa, Nicola Giuliani

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. Firstly, 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 to 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 pre-osteocyte autophagic death was triggered during co-culturing 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 identified osteocyte autophagy as a new potential target in MM bone disease and supported the use of PIs to increase osteocyte viability and improve bone integrity in MM patients. This article is protected by copyright. All rights reserved.