Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib

作者：Nakamura Shingen; Miki Hirokazu; Kido Shinsuke; Nakano Ayako; Hiasa Masahiro; Oda Asuka; Amou Hiroe; Watanabe Keiichiro; Harada Takeshi; Fujii Shiro; Takeuchi Kyoko; Kagawa Kumiko; Ozaki Shuji; Matsumoto Toshio; Abe Masahiro^*

来源：International Journal of Hematology, 2013, 98(1): 66-73.

DOI：10.1007/s12185-013-1367-z

• Myeloma
• ER stress
• Bortezomib
• Proteasome inhibitor
• Activating transcription factor 4
• Osteoblastogenesis

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 beta-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).

• 出版日期2013-7