ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation
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(2020) 11:516
RESEARCH
Open Access
ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation Dan Zhang1†, Kim De Veirman2†, Rong Fan1,2†, Qiang Jian1, Yuchen Zhang3, Li Lei1, Holly Evans4, Yanmeng Wang1,2, Lei Lei1, Baiyan Wang5, Ramone A. Williamson1, Andrew Chantry4, Pengcheng He6, Ang Li7, Hendrik De Raeve8, Karin Vanderkerken2, Aili He5 and Jinsong Hu1*
Abstract Background: Bone destruction is a hallmark of multiple myeloma (MM). It has been reported that proteasome inhibitors (PIs) can reduce bone resorption and increase bone formation in MM patients, but the underlying mechanisms remain unclear. Methods: Mesenchymal stem cells (MSCs) were treated with various doses of PIs, and the effects of bortezomib or carfilzomib on endoplasmic reticulum (ER) stress signaling pathways were analyzed by western blotting and realtime PCR. Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were used to determine the osteogenic differentiation in vitro. Specific inhibitors targeting different ER stress signaling and a Tet-on inducible overexpressing system were used to validate the roles of key ER stress components in regulating osteogenic differentiation of MSCs. Chromatin immunoprecipitation (ChIP) assay was used to evaluate transcription factorpromoter interaction. MicroCT was applied to measure the microarchitecture of bone in model mice in vivo. Results: We found that both PERK-ATF4 and IRE1α-XBP1s ER stress branches are activated during PI-induced osteogenic differentiation. Inhibition of ATF4 or XBP1s signaling can significantly impair PI-induced osteogenic differentiation. Furthermore, we demonstrated that XBP1s can transcriptionally upregulate ATF4 expression and overexpressing XBP1s can induce the expression of ATF4 and other osteogenic differentiation-related genes and therefore drive osteoblast differentiation. MicroCT analysis further demonstrated that inhibition of XBP1s can strikingly abolish bortezomib-induced bone formation in mouse. Conclusions: These results demonstrated that XBP1s is a master regulator of PI-induced osteoblast differentiation. Activation of IRE1α-XBP1s ER stress signaling can promote osteogenesis, thus providing a novel strategy for the treatment of myeloma bone disease. Keywords: Proteasome inhibitor, Multiple myeloma, Mesenchymal stem cell, Xbp1s, Osteogenic differentiation
* Correspondence: [email protected] † Dan Zhang, Kim De Veirman and Rong Fan contributed equally to this work. 1 Department of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi’an 710061, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate
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