ER stress disrupts hypertrophic chondrocytes plasticity, impairing trabecular organization and vascularization
Dr. Xiaodan Yu (Post-doctoral Fellow)
[Supervisor: Professor Kathryn Cheah]

The cellular dynamics of the bone remodeling niche are critical for homeostasis and repair. Hypertrophic chondrocytes (HCs) contribute to osteoblasts, but their plasticity under stress remains undefined. Here, we integrate single-cell and spatial transcriptomics in an MCDS mouse model (13del mice) to decode HC fate under ER stress. Stressed HCs revert to a pre-hypertrophic-like state with disrupted differentiation, impairing contribution to osteoblast and skeletal stem/progenitor lineages. This disorganizes trabecular structure, coupled with abnormal osteoclast distribution and disrupted type H vessel formation. Mechanistically, unresolved ER stress upregulates Serpinf1 and induces ectopic SOX9 expression in trabecular bone. Genetic removal of Sox9 in HCs partially restores differentiation and bone formation, while Atf4 overexpression phenocopies this disruption. Our findings establish ER stress as a regulator of HC plasticity, defining a "lineage stress" mechanism underlying skeletal disorders and identifying the ER stress-SOX9 axis as a potential therapeutic target.

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