The integrated stress response in skeletal development and disease
School of Biomedical Sciences, University of Hong Kong, 5 Sassoon Rd, Hong Kong.
The integrated stress response (ISR) has a central role in maintaining homeostasis in cells experiencing many forms of cellular stress such as biomechanical loading, oxidative stress, hypoxia, endoplasmic reticulum (ER) stress. Induction of the ISR is important for maintaining cells in normal development and is associated with diverse congenital and common diseases. Human congenital skeletal dysplasia caused by disrupted development of the growth plate is often associated with mutations that trigger ER stress that induces the Unfolded Protein Response (UPR). Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide mechanistic insight into the impact of the ISR on cell fate. We show that the ISR core protein kinase RNA-like ER kinase (PERK) signaling pathway that modulates translation, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4 directed transactivation of Sox9. 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 may be a therapeutic strategy for stress-induced skeletal disorders.