Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia

ELife
Cheng WangKathryn S E Cheah

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.

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Citations

Feb 16, 2019·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Shireen R Lamandé, John F Bateman
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Datasets Mentioned

BETA
GSE99306

Methods Mentioned

BETA
nucleotide exchange
transgenic
ChIP-seq
ChIP-PCR
ChIP
transfection
genotyping
PCR
immunoprecipitation
Assay

Software Mentioned

Bowtie
ISRIB
R Bioconductor package
DAVID
Picard
HOMER
David Web Tools

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