XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.
XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.
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DOI：
10.1371/journal.pgen.1005505
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Bateman JF
中科院分区：
文献类型：
--
作者：
Cameron TL;Bell KM;Gresshoff IL;Sampurno L;Mullan L;Ermann J;Glimcher LH;Boot-Handford RP;Bateman JF
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 (ColX N617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1 CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColX N617K, 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. A significant component of the molecular pathology of many inherited skeletal disorders caused by mutations that cause misfolding and intracellular retention of extracellular matrix proteins is the induction of a cellular response to endoplasmic reticulum stress called the unfolded protein response (UPR). In the case of Schmid metaphyseal chondrodysplasia (MCDS) caused by collagen X misfolding mutations, the consequences of the UPR have been shown to be the central cause of the cartilage pathology. Thus understanding the involvement of canonical UPR sensors, IRE1, ATF6, and PERK and their downstream signalling effects on chondrocyte differentiation and function is important for defining disease mechanisms and devising new therapies. Using a mouse model expressing misfolding collagen X and lacking IRE1/XBP1 pathway activity in chondrocytes, we demonstrate that this highly conserved UPR pathway is redundant to the cartilage pathology thus implicating XBP1-independent UPR signalling pathways. Based on detailed analysis of gene expression patterns we propose that XBP1-independent UPR driven disruption of C/EBP-β, a master regulator of chondrocyte differentiation, is important for the pathophysiology. Strategies designed to modulate C/EBP-β activity may thus offer therapeutic opportunities.
