Proteasome inhibitors blunt myeloma induced osteocyte death targeting autophagy both in vitro and in vivo in multiple myeloma patients
Year: 2015
Type: dissertation
Abstract: Multiple myeloma (MM) is characterized by severe bone destruction. Recently it has been shown that an increased osteocyte death is involved in MM‐induced osteolysis. In this study we show that autophagy rather than apoptosis is involved in MM‐induced osteocyte death and that proteasome inhibitors (PI)s, a class of drugs known to stimulate osteoblast formation, significantly blunted MM‐induced osteocyte and pre‐osteocyte death. PIs also reduced osteocyte death induced by high dose of dexamethasone (DEX) and potentiated the anabolic effect of PTH(1‐34). PIs, such as Bortezomib (BOR), are able to block the autophagic process in osteocytes and pre‐osteocytes, as shown by an increased of the level of the autophagic marker LC3 and a decreased of p62. Moreover, both MM‐induced and DEX‐induced autophagic cell death were blunted by PIs. Transmission electron microscopy and confocal microscopy evaluation confirmed observations. These data were further expanded in vivo by a histological analysis of osteocyte viability on bone biopsies in MM patients. A significant increase in the number of viable osteocytes was demonstrated in patients treated with Bortezomib (BOR)‐based regimen as compared to those treated with other regimen. Our data identify osteocyte autophagy as a potential target in MM bone disease and support the use of PIs to increase osteocyte viability and improve bone integrity in MM patients.
Author: Toscani, Denise
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1904787405