RRC ID 62312
Author Wang C, Tan Z, Niu B, Tsang KY, Tai A, Chan WCW, Lo RLK, Leung KKH, Dung NWF, Itoh N, Zhang MQ, Chan D, Cheah KSE.
Title Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia.
Journal Elife
Abstract The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.
Volume 7
Published 2018-7-19
DOI 10.7554/eLife.37673
PII 37673
PMID 30024379
PMC PMC6053305
MeSH Acetamides / administration & dosage Acetamides / pharmacology Activating Transcription Factor 4 / metabolism Animals Apoptosis / drug effects Base Sequence Cell Differentiation* / drug effects Cell Survival / drug effects Chondrocytes / metabolism Chondrocytes / pathology* Chondrogenesis Cyclohexylamines / administration & dosage Cyclohexylamines / pharmacology Endoplasmic Reticulum Stress / drug effects Eukaryotic Initiation Factor-2 / metabolism Fibroblast Growth Factors / metabolism Growth Plate / abnormalities Growth Plate / drug effects Growth Plate / pathology Hypertrophy Mice, Inbred C57BL Models, Biological Osteochondrodysplasias / pathology* Phenotype SOX9 Transcription Factor / metabolism Signal Transduction Stress, Physiological* / drug effects Transcription Factor CHOP / metabolism Transcriptome / genetics Unfolded Protein Response / drug effects eIF-2 Kinase / metabolism
IF 7.551
Resource
Human and Animal Cells ATDC5(RCB0565)