XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease

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A significant component of the molecular pathology of many inherited skeletal disorders caused by mutations that cause misfolding and intracellular retention of extracellular matrix proteins is the induction of a cellular response to endoplasmic reticulum stress called the unfolded protein response (UPR). In the case of Schmid metaphyseal chondrodysplasia (MCDS) caused by collagen X misfolding mutations, the consequences of the UPR have been shown to be the central cause of the cartilage pathology. Thus understanding the involvement of canonical UPR sensors, IRE1, ATF6, and PERK and their downstream signalling effects on chondrocyte differentiation and function is important for defining disease mechanisms and devising new therapies. Using a mouse model expressing misfolding collagen X and lacking IRE1/XBP1 pathway activity in chondrocytes, we demonstrate that this highly conserved UPR pathway is redundant to the cartilage pathology thus implicating XBP1-independent UPR signalling pathways. Based on detailed analysis of gene expression patterns we propose that XBP1-independent UPR driven disruption of C/EBP-β, a master regulator of chondrocyte differentiation, is important for the pathophysiology. Strategies designed to modulate C/EBP-β activity may thus offer therapeutic opportunities.

Vyšlo v časopise: XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005505
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005505

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