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The IRE1-XBP1s Axis Drives Inflammatory Osteolysis by Regulating a 5-HT Dependent Endogenous Anti-Autophagy Mechanism
Pengchao Yang1,2, Binxiang Zhu3, Yuzhi He1
1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 23, 2026
Summary
This study reveals the IRE1-XBP1s pathway regulates inflammatory osteoclastogenesis and bone loss by controlling 5-HT transport and autophagy. Inhibiting this axis offers a potential therapeutic strategy for inflammatory bone diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Inflammatory osteolysis involves osteoclast activation and disrupted bone remodeling.
- The IRE1-XBP1s axis, a key unfolded protein response pathway, is crucial for cellular homeostasis.
- Its specific role in inflammatory osteoclastogenesis was previously unknown.
Purpose of the Study:
- To investigate the role of the IRE1-XBP1s axis in inflammatory osteoclastogenesis and osteolysis.
- To elucidate the molecular mechanisms linking IRE1-XBP1s to osteoclast formation.
- To explore the therapeutic potential of targeting this pathway for inflammatory bone loss.
Main Methods:
- Single-cell RNA-seq and RNA-seq analysis of LPS-induced osteolysis models.
- In vitro and in vivo inhibition of the IRE1-XBP1s axis.
- Dual-luciferase assays and ChIP-PCR to assess transcriptional regulation.
- Untargeted metabolomics and HPLC-MS for metabolic profiling.
- Assessment of patient-derived peripheral blood mononuclear cells (PBMCs).
Main Results:
- Single-cell RNA-seq identified increased osteoclast precursors and activated IRE1-XBP1s in osteolysis.
- IRE1-XBP1s inhibition reduced osteoclastogenesis and bone loss.
- Blocking IRE1-XBP1s suppressed Slc6a4 transcription, impacting 5-HT transport.
- Escitalopram (5-HT transporter inhibitor) also inhibited osteoclastogenesis.
- 5-HT attenuated autophagy and osteoclast differentiation, mediated by 3-methyladenine (3MA) metabolism.
- Targeting the IRE1-XBP1s-Slc6a4 axis reduced pro-osteoclastogenic effects in patient-derived cells.
Conclusions:
- The IRE1-XBP1s axis is a critical regulator of inflammatory osteoclastogenesis and osteolysis.
- This pathway influences osteoclast formation via 5-HT transport and an anti-autophagy mechanism.
- Inhibition of the IRE1-XBP1s-Slc6a4 axis presents a promising therapeutic avenue for inflammatory bone loss conditions.
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