ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation

Dan Zhang, Kim De Veirman, Rong Fan, Qiang Jian, Yuchen Zhang, Li Lei, Holly Evans, Yanmeng Wang, Lei Lei, Baiyan Wang, Ramone A Williamson, Andrew Chantry, Pengcheng He, Ang Li, Hendrik De Raeve, Karin Vanderkerken, Aili He, Jinsong Hu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 real-time 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 factor-promoter 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.

Original languageEnglish
Article number516
Number of pages13
JournalStem Cell Research & Therapy
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Mesenchymal stem cell
  • Multiple myeloma
  • Osteogenic differentiation
  • Proteasome inhibitor
  • Xbp1s

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