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

Cheng Wang1, Zhijia Tan1, Ben Niu1

  • 1School of Biomedical Sciences, University of Hong Kong, Hong Kong, China.

Elife
|July 20, 2018
PubMed

Insights

The integrated stress response (ISR) pathway, specifically PERK signaling, disrupts chondrocyte differentiation in skeletal disorders. Inhibiting this pathway rescues differentiation and ameliorates MCDS in mice.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The integrated stress response (ISR) is a cellular pathway activated by various stresses, including endoplasmic reticulum (ER) stress.
  • Dysregulation of the ISR is implicated in various diseases, but its precise role in cell differentiation, particularly in skeletal development, remains unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the ISR influences cell fate and differentiation.
  • To explore the role of the PERK pathway within the ISR in chondrodysplasia, using a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS).

Main Methods:

  • Utilized a mouse model of MCDS to study ISR-mediated effects on chondrocyte differentiation.
  • Analyzed the involvement of the PERK pathway, ATF4, and CHOP in regulating chondrocyte differentiation and gene expression (Sox9, Fgf21).
  • Administered a chemical inhibitor of PERK signaling to mutant mice.

Main Results:

  • The PERK pathway, leading to ATF4 and CHOP synthesis, was identified as a key driver of dysplasia by reversing chondrocyte differentiation through ATF4-mediated Sox9 transactivation.
  • CHOP and dual CHOP-ATF4 transactivation of Fgf21 were found to be crucial for chondrocyte survival.
  • Inhibition of PERK signaling in mutant mice successfully prevented differentiation defects and improved chondrodysplasia.

Conclusions:

  • Aberrant chondrocyte differentiation, driven by the PERK-ATF4-Sox9 axis, is a central mechanism in MCDS.
  • Targeted inhibition of the ISR, specifically PERK signaling, represents a potential therapeutic strategy for stress-induced skeletal disorders.
  • Understanding the ISR's impact on cell fate offers new avenues for treating chondrodysplasias.
Keywords:
ATF4ISRIBchondrodysplasiadevelopmental biologyendoplasmic reticulum stressintegrated stress responsemouseprotein kinase RNA-like ER kinase pathway

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