RRC ID 44456
Author Nakamura S, Miki H, Kido S, Nakano A, Hiasa M, Oda A, Amou H, Watanabe K, Harada T, Fujii S, Takeuchi K, Kagawa K, Ozaki S, Matsumoto T, Abe M.
Title Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib.
Journal Int J Hematol
Abstract Endoplasmic reticulum (ER) stress is induced in matrix-producing osteoblasts and plays an essential role in osteoblastogenesis. Although the bone anabolic activity of proteasome inhibitors has been demonstrated, the roles of ER stress induced by proteasome inhibition in osteoblastogenesis remain largely unknown. Here we show that bortezomib translationally increases protein levels of activating transcription factor 4 (ATF4), a downstream mediator of ER stress, in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells. The suppression of ATF4 expression by siRNA abrogated osteocalcin expression and mineralized nodule formation by MC3T3-E1 cells induced by bortezomib, indicating a critical role for ATF4 in bortezomib-mediated osteoblastogenesis. However, bortezomib at 20 nM or higher abolished the mineralized nodule formation along with reductions in the expression of osteoblastogenesis mediators β-catenin and Osterix. Furthermore, at 50 nM, bortezomib induced the expression of C/EBP homologous protein (CHOP), suggesting activation of the ATF4-CHOP pro-apoptotic pathway. These results suggest that a low dose of bortezomib induces osteogenic activity, but that, in contrast, excessive ER stress caused by bortezomib at higher doses hampers osteoblastogenesis. Therefore, dosing schedules for proteasome inhibitors warrant further study to maximize anabolic actions without compromising anti-MM activity in patients with multiple myeloma (MM).
Volume 98(1)
Pages 66-73
Published 2013-7-1
DOI 10.1007/s12185-013-1367-z
PMID 23708974
MeSH 3T3 Cells Activating Transcription Factor 4 / antagonists & inhibitors Activating Transcription Factor 4 / genetics Activating Transcription Factor 4 / metabolism* Animals Antineoplastic Agents / adverse effects Antineoplastic Agents / pharmacology Biomarkers / metabolism Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Bone Marrow Cells / pathology Boronic Acids / adverse effects* Boronic Acids / pharmacology Bortezomib Calcification, Physiologic / drug effects Cells, Cultured Endoplasmic Reticulum Stress / drug effects* Gene Expression Regulation / drug effects Gene Silencing Humans Mice Multiple Myeloma / drug therapy Multiple Myeloma / metabolism Multiple Myeloma / pathology Neoplasm Proteins / antagonists & inhibitors Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Osteoblasts / drug effects* Osteoblasts / physiology Osteocalcin / genetics Osteocalcin / metabolism Osteogenesis / drug effects* Proteasome Inhibitors / adverse effects* Proteasome Inhibitors / pharmacology Pyrazines / adverse effects* Pyrazines / pharmacology RNA, Small Interfering / metabolism Stromal Cells / drug effects Stromal Cells / physiology
IF 2.245
Times Cited 3
Human and Animal Cells ST2(RCB0224) MC3T3-E1(RCB1126)