XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease

• Published in: PLoS genetics Vol. 11; no. 9; p. e1005505
• Main Authors: Cameron, Trevor L, Bell, Katrina M, Gresshoff, Irma L, Sampurno, Lisa, Mullan, Lorna, Ermann, Joerg, Glimcher, Laurie H, Boot-Handford, Raymond P, Bateman, John F
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2015; Public Library of Science (PLoS)
• Subjects: Animals; Bone Diseases - pathology; Cartilage cells; CCAAT-Enhancer-Binding Protein-beta - antagonists & inhibitors; CCAAT-Enhancer-Binding Protein-beta - physiology; Cell Differentiation - physiology; Chondrocytes - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Gene Expression Profiling; Health aspects; Mice; Mice, Transgenic; Musculoskeletal diseases; Physiological aspects; Regulatory Factor X Transcription Factors; Transcription Factors - genetics; Transcription Factors - physiology; Unfolded Protein Response - physiology; X-Box Binding Protein 1
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005505

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.