Different Forms of ER Stress in Chondrocytes Result in Short Stature Disorders and Degenerative Cartilage Diseases: New Insights by Cartilage-Specific ERp57 Knockout Mice.

Yvonne Rellmann,Rita Dreier

doi:10.1155/2018/8421394

Abstract

Cartilage is essential for skeletal development by endochondral ossification. The only cell type within the tissue, the chondrocyte, is responsible for the production of macromolecules for the extracellular matrix (ECM). Before proteins and proteoglycans are secreted, they undergo posttranslational modification and folding in the endoplasmic reticulum (ER). However, the ER folding capacity in the chondrocytes has to be balanced with physiological parameters like energy and oxygen levels. Specific cellular conditions, e.g., a high protein demand, or pathologic situations disrupt ER homeostasis and lead to the accumulation of poorly folded or misfolded proteins. This state is called ER stress and induces a cellular quality control system, the unfolded protein response (UPR), to restore homeostasis. Different mouse models with ER stress in chondrocytes display comparable skeletal phenotypes representing chondrodysplasias. Therefore, ER stress itself seems to be involved in the pathogenesis of these diseases. It is remarkable that chondrodysplasias with a comparable phenotype arise independent from the sources of ER stress, which are as follows: (1) mutations in ECM proteins leading to aggregation, (2) deficiencies in ER chaperones, (3) mutations in UPR signaling factors, or (4) deficiencies in the degradation of aggregated proteins. In any case, the resulting UPR substantially impairs ECM protein synthesis, chondrocyte proliferation, and/or differentiation or regulation of autophagy and apoptosis. Notably, chondrodysplasias arise no matter if single or multiple events are affected. We analyzed cartilage-specific ERp57 knockout mice and demonstrated that the deficiency of this single protein disulfide isomerase, which is responsible for formation of disulfide bridges in ECM glycoproteins, is sufficient to induce ER stress and to cause an ER stress-related bone phenotype. These mice therefore qualify as a novel model for the analysis of ER stress in chondrocytes. They give new insights in ER stress-related short stature disorders and enable the analysis of ER stress in other cartilage diseases, such as osteoarthritis.

Highlights

Cartilage is essential for skeletal development by endochondral ossification
It is remarkable that chondrodysplasias with a comparable phenotype arise independent from the sources of endoplasmic reticulum (ER) stress, which are as follows: (1) mutations in extracellular matrix (ECM) proteins leading to aggregation, (2) deficiencies in ER chaperones, (3) mutations in unfolded protein response (UPR) signaling factors, or (4) deficiencies in the degradation of aggregated proteins
To get a well-defined overview about mouse models with ER stress in chondrocytes, one should discriminate between (1) transgenic mice with mutations in genes encoding ECM proteins, (2) transgenic mice with mutations in genes encoding exogenous proteins that are normally not expressed in cartilage, (3) mice with a knockout of genes encoding proteins of the ER folding machinery, (4) mice with a knockout of genes of UPR signaling factors, (5) mice with a knockout of proteins involved in the degradation of aggregated proteins, and (6) mice with a knockout of proteins essential for protein trafficking and secretion

Summary

Introduction

Cartilage is essential for skeletal development by endochondral ossification. The only cell type within the tissue, the chondrocyte, is responsible for the production of macromolecules for the extracellular matrix (ECM). To get a well-defined overview about mouse models with ER stress in chondrocytes, one should discriminate between (1) transgenic mice with mutations in genes encoding ECM proteins, (2) transgenic mice with mutations in genes encoding exogenous proteins that are normally not expressed in cartilage, (3) mice with a knockout of genes encoding proteins of the ER folding machinery, (4) mice with a knockout of genes of UPR signaling factors, (5) mice with a knockout of proteins involved in the degradation of aggregated proteins, and (6) mice with a knockout of proteins essential for protein trafficking and secretion.

Results

Conclusion