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

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.

K+ and Ca2+ Channels Regulate Ca2+ Signaling in Chondrocytes: An Illustrated Review

“…Progress towards understanding chondrocyte physiology, the progressive changes with aging, and osteoarthritis [ 119 ] is likely to require further work on the progenitor or stem cell population of chondrocytes [ 78 , 87 ] and may benefit from recent advances in detecting and analyzing extracellular vesicles that are released from chondrocytes and contain very important molecular signatures [ 120 ] for ion channels or intracellular signaling pathways. It also seems possible that integrating important new findings that characterize ER stress in chondrocytes with the concepts that are diagramed in Figure 6 will be informative [ 121 ].…”

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

“…Mitochondrial DNA haplogroups are correlated with the risk of knee OA, and also affect oxidative stress and the survival of cybrid cells [9]. The loss of endoplasmic reticulum (ER) chaperones increase ER stress, downregulating cartilage ECM synthesis in osteoarthritic joints [10]. Increased ER stress is present in articular chondrocytes in unilateral anterior cross-bite-mediated OA in mice [11].…”

ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation

“…Only correctly folded proteins move via vesicular transport to the Golgi apparatus, where additional modifications occur and sorting into vesicles is established. This enables further transport to different cellular compartments or secretion into the extracellular space [ 7 ].…”

“…In growth plate cartilage, the UPR also induces changes in differentiation and cell-cycle progression of hypertrophic chondrocytes [ 11 ]. Because hypertrophic differentiation and apoptotic cell death are hallmarks of OA [ 12 , 13 ], a proper ER function in chondrocytes is not only essential for effective protein synthesis and secretion into the ECM, but could also prevent cartilage degeneration [ 7 ].…”