ArticleInternational journal of hematology2013
Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib.
Article in International journal of hematology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 34 citations in OpenAlex.
- Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.International journal of hematology · 2023Article
- Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.Journal of bone and mineral metabolism · 2023Review
- Folate ameliorates homocysteine-induced osteoblast dysfunction by reducing endoplasmic reticulum stress-activated PERK/ATF-4/CHOP pathway in MC3T3-E1 cells.Journal of bone and mineral metabolism · 2022Article
- Lansoprazole-induced osteoporosis via the IP3R- and SOCE-mediated calcium signaling pathways.Molecular medicine (Cambridge, Mass.) · 2022Article
- Treatment of Gout with TCM Using Turmeric and Corn Silk: A Concise Review Article and Pharmacology Network Analysis.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- GPX7 Facilitates BMSCs Osteoblastogenesis via ER Stress and mTOR Pathway.Journal of cellular and molecular medicine · 2021Article
- ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation.Stem cell research & therapy · 2020Article
- Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics.World journal of stem cells · 2014Review
- Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells.International journal of hematology · 2014Article
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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).
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