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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.<\/jats:p>","DOI":"10.7554\/elife.37673","type":"journal-article","created":{"date-parts":[[2018,7,18]],"date-time":"2018-07-18T11:09:34Z","timestamp":1531912174000},"source":"Crossref","is-referenced-by-count":79,"title":["Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia"],"prefix":"10.7554","volume":"7","author":[{"given":"Cheng","family":"Wang","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2295-5169","authenticated-orcid":true,"given":"Zhijia","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, 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L K","family":"Lo","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith K H","family":"Leung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson W F","family":"Dung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Itoh","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, University of Kyoto, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-1830","authenticated-orcid":true,"given":"Michael 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