ArticleStem cell research & therapy2020
ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation.
Article in Stem cell research & therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 49 citations in OpenAlex.
- Cell-Penetrating Peptide-Mediated Modulation of Endoplasmic Reticulum Stress: A Bioengineered and Translational Approach.ACS pharmacology & translational science · 2026Review
- Arsenic disrupts autophagosome-lysosome fusion in a zinc dependent manner across multiple human skin and lung cells lines.Archives of toxicology · 2026Article
- CircTspan3 Promotes Cartilage Development Through ANNEXIN A2-Mediated Ferroptosis and Apoptosis Inhibition and Exosome-Mediated Paracrine Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The role of the unfolded protein response pathway in bone homeostasis and potential therapeutic target in cancer-associated bone disease.Bone research · 2025Review
- IRE1α pathway: A potential bone metabolism mediator.Cell proliferation · 2024Review
- Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.The Journal of biological chemistry · 2024Article
- The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.The Journal of clinical investigation · 2024Article
- Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.International journal of molecular sciences · 2024Review
- ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.Journal of cellular physiology · 2024Article
- Chronic arsenic exposure suppresses proteasomal and autophagic protein degradation.Environmental toxicology and pharmacology · 2024Article
- Article
- Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis.Journal of translational medicine · 2023Review
- Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism.Cell reports · 2023Article
- The Role of XBP1 in bone metabolism.Frontiers in endocrinology · 2023Review
- Review
- Review
- Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts.International journal of molecular sciences · 2021Review
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Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundBone 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.
methodsMesenchymal 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.
resultsWe 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.
conclusionsThese 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.
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