2. Academic Validation
  3. ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation

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

  • Stem Cell Res Ther. 2020 Nov 30;11(1):516. doi: 10.1186/s13287-020-02037-3.
Dan Zhang 1,  Kim De Veirman 2,  Rong Fan 1 2,  Qiang Jian 1,  Yuchen Zhang 3,  Li Lei 1,  Holly Evans 4,  Yanmeng Wang 1 2,  Lei Lei 1,  Baiyan Wang 5,  Ramone A Williamson 1,  Andrew Chantry 4,  Pengcheng He 6,  Ang Li 7,  Hendrik De Raeve 8,  Karin Vanderkerken 2,  Aili He 5,  Jinsong Hu 9
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, 710061, China.
  • 2 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium.
  • 3 Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
  • 4 Sheffield Myeloma Research Team, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK.
  • 5 Department of Clinical Hematology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 6 Department of Clinical Hematology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
  • 7 Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China.
  • 8 Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, 1090, Brussels, Belgium.
  • 9 Department of Cell Biology and Genetics, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, 710061, China. jinsong.hu@xjtu.edu.cn.
PMID: 33256835 DOI: 10.1186/s13287-020-02037-3
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.

Keywords

Mesenchymal stem cell; Multiple myeloma; Osteogenic differentiation; Proteasome inhibitor; Xbp1s.

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