The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients.
The proteasome inhibitor bortezomib may increase osteoblast-related markers in multiple myeloma (MM) patients; however, its potential osteoblastic stimulatory effect is not known. In this study, we show that bortezomib significantly induced a stimulatory effect on osteoblast markers in human mesenchymal cells without affecting the number of osteoblast progenitors in bone marrow cultures or the viability of mature osteoblasts. Consistently we found that bortezomib significantly increased the transcription factor Runx2/Cbfa1 activity in human osteoblast progenitors and osteoblasts without affecting nuclear and cytoplasmatic active beta-catenin levels. Consequently a stimulatory effect of bortezomib on bone nodule formation was also demonstrated in osteoblast progenitors. These in vitro observations were confirmed in vivo by the finding of a significant increase in the number of osteoblastic cells x mm(2) of bone tissue and in the number of Runx2/Cbfa1-positive osteoblastic cells that was observed in MM patients who responded to bortezomib. Our in vitro and in vivo observations support the hypothesis that a direct stimulatory effect on bone formation process could occur during bortezomib treatment.
Giuliani
Nicola
N
Hematology and Bone Marrow Transplantation Center, Department of Internal Medicine and Biomedical Science, University of Parma, Parma, Italy. nicola.giuliani@unipr.it
Morandi
Francesca
F
Tagliaferri
Sara
S
Lazzaretti
Mirca
M
Bonomini
Sabrina
S
Crugnola
Monica
M
Mancini
Cristina
C
Martella
Eugenia
E
Ferrari
Luca
L
Tabilio
Antonio
A
Rizzoli
Vittorio
V
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D023081:CCAAT-Binding Factor; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D023081:CCAAT-Binding Factor; D050659:Core Binding Factor Alpha 1 Subunit; D011480:Protease Inhibitors; D011719:Pyrazines; C493709:RUNX2 protein, human; D000069286:Bortezomib