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dc.contributor.authorCameron, TL
dc.contributor.authorBell, KM
dc.contributor.authorGresshoff, IL
dc.contributor.authorSampurno, L
dc.contributor.authorMullan, L
dc.contributor.authorErmann, J
dc.contributor.authorGlimcher, LH
dc.contributor.authorBoot-Handford, RP
dc.contributor.authorBateman, JF
dc.date.accessioned2021-02-04T00:12:54Z
dc.date.available2021-02-04T00:12:54Z
dc.date.issued2015-09-01
dc.identifierpii: PGENETICS-D-15-00864
dc.identifier.citationCameron, T. L., Bell, K. M., Gresshoff, I. L., Sampurno, L., Mullan, L., Ermann, J., Glimcher, L. H., Boot-Handford, R. P. & Bateman, J. F. (2015). XBP1-Independent UPR Pathways Suppress C/EBP-beta Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease. PLOS GENETICS, 11 (9), https://doi.org/10.1371/journal.pgen.1005505.
dc.identifier.issn1553-7404
dc.identifier.urihttp://hdl.handle.net/11343/259056
dc.description.abstractSchmid 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.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleXBP1-Independent UPR Pathways Suppress C/EBP-beta Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pgen.1005505
melbourne.affiliation.departmentPaediatrics (RCH)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titlePLoS Genetics
melbourne.source.volume11
melbourne.source.issue9
dc.rights.licenseCC BY
melbourne.elementsid1198555
melbourne.contributor.authorBateman, John
dc.identifier.eissn1553-7404
melbourne.accessrightsOpen Access


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