ArticlePLoS genetics2015
XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 53 citations in OpenAlex.
- 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 circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism.Journal of advanced research · 2024Article
- IRE1α pathway: A potential bone metabolism mediator.Cell proliferation · 2024Review
- IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization.Genes & diseases · 2024Article
- IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis.Experimental & molecular medicine · 2023Article
- CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia.International journal of molecular sciences · 2023Article
- Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology.Connective tissue research · 2022Review
- Role of autophagy in intervertebral disc and cartilage function: implications in health and disease.Matrix biology : journal of the International Society for Matrix Biology · 2021Review
- Differentiation of Hypertrophic Chondrocytes from Human iPSCs for the In Vitro Modeling of Chondrodysplasias.Stem cell reports · 2021Article
- ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation.Stem cell research & therapy · 2020Article
- Genetic Disorders of the Extracellular Matrix.Anatomical record (Hoboken, N.J. : 2007) · 2020Review
- MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint.Autophagy · 2020Article
- New developments in chondrocyte ER stress and related diseases.F1000Research · 2020Review
- XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease.PLoS genetics · 2019Article
- Targeting defective proteostasis in the collagenopathies.Current opinion in chemical biology · 2019Review
- Effect of rapamycin on bone mass and strength in the α2(I)-G610C mouse model of osteogenesis imperfecta.Journal of cellular and molecular medicine · 2019Article
- Gene cloning to clinical trials-the trials and tribulations of a life with collagen.International journal of experimental pathology · 2019Review
- Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.EBioMedicine · 2019Article
- Article
- 5,7,3',4'-Tetramethoxyflavone protects chondrocytes from ER stress-induced apoptosis through regulation of the IRE1α pathway.Connective tissue research · 2018Article
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities.
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