The proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cells.
OBJECTIVE
Bortezomib (PS-341; Velcade), a proteasome inhibitor, is used as a therapeutic agent for multiple myeloma. Bortezomib has been shown to strongly induce osteoblast differentiation and elevate the levels of osteoblast-related differentiation markers in the serum of patients with myeloma. Bortezomib also reportedly increases the activity of the transcription factor, Runx2. However, the mechanism of action by which bortezomib-elevated Runx2 activity mediates osteoblast differentiation remains unclear. On the other hand, fibroblast growth factor 2 (FGF-2) is found at high levels in patients with multiple myeloma. We previously reported that FGF-2 reduces the levels of the transcriptional coactivator with PDZ-binding motif (TAZ). We therefore investigated the effects of bortezomib on TAZ protein levels in the presence of FGF-2.


METHODS
Osteoblastic MC3T3-E1 cells were treated with different concentrations of bortezomib in the presence or absence of FGF-2 and various biologic responses were investigated by immunoblotting, RT-PCR, quantitative PCR, and alizarin red staining.


RESULTS
We found that bortezomib inhibited FGF-2-induced reduction of TAZ levels through a pathway other than that used for proteasome inhibition, while maintaining TAZ function, which in turn, enhanced the expression of Runx2-transcribed osteogenic differentiation markers. Bortezomib also suppressed the antimineralization effect of FGF-2.


CONCLUSIONS
These findings suggest that bortezomib inhibited FGF-2-induced reduction of TAZ and consequently stimulated osteogenic differentiation independently of proteasome inhibition. These findings may contribute to elucidate the osteolytic mechanism in multiple myeloma, and to the development of new drugs for multiple myeloma and other osteolytic diseases.
Eda
Homare
H
Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan.
Aoki
Katsuhiko
K
Kato
Soki
S
Okawa
Yutaka
Y
Takada
Koji
K
Tanaka
Takaaki
T
Marumo
Keishi
K
Ohkawa
Kiyoshi
K
D016475:3T3 Cells; D000217:Acyltransferases; D000818:Animals; D001483:Base Sequence; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy / Q000209:etiology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D001897:Boronic Acids; D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D000069286:Bortezomib; D000217:Acyltransferases; C486363:tafazzin protein, mouse