Abstract
As chondrocytes are highly secretory and they experience a variety of stresses, physiological unfolded protein response (UPR) signalling is essential for extracellular matrix (ECM) secretion and chondrogenesis. In the three branches of the UPR pathway, PERK governs the translational attenuation and transcriptional upregulation of amino acid and redox metabolism and induction of apoptosis. It was previously demonstrated that a defect of the PERK branch of the UPR signalling pathway causes the accumulation of unfolded proteins, leading to cell death without perturbing endoplasmic reticulum (ER)-to-Golgi transport in pancreatic β cells. However, little is known about the role of PERK in chondrocytes. In this study, we found that PERK signalling is activated in chondrocytes, and inhibition of PERK reduces collagen secretion despite causing excessive collagen synthesis in the ER. Perk−/− mice displayed reduced collagen in articular cartilage but no differences in chondrocyte proliferation or apoptosis compared to the findings in wild-type mice. PERK inhibition increases misfolded protein levels in the ER, which largely hinder ER-to-Golgi transport. These results suggest that the translational control mediated by PERK is a critical determinant of ECM secretion in chondrocytes.
Highlights
Cartilage is characterised by a structurally arranged extracellular matrix (ECM) composed of collagen and non-collagenous proteins such as proteoglycans[1,2]
The levels of phosphorylated PERK and eIF2α were increased by 1.6- and 2.8-fold in the differentiated ATDC5 cells, respectively, and the expression of ATF4 and CHOP was increased by 2.2- and 3.5-fold, respectively, indicating PERK pathway activation (Fig. 1C)
These results demonstrated that chondrocyte differentiation in ATDC5 cells activates the three branches of the unfolded protein response (UPR), among which the PERK pathway was most significantly activated
Summary
Cartilage is characterised by a structurally arranged extracellular matrix (ECM) composed of collagen and non-collagenous proteins such as proteoglycans[1,2]. As chondrocytes are highly secretory and they experience a variety of stresses, physiological UPR signalling appears essential for ECM secretion and chondrogenesis[9,10,11]. Mice with cartilage-specific knockout of ATF4, which is a downstream transcription factor of PERK signalling, displayed a short stature and delayed endochondral ossification[19]. The contribution of PERK to chondrocyte differentiation and ECM secretion has not been extensively investigated
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