Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Münster, Germany.
Oxid Med Cell Longev. 2018 Dec 17;2018:8421394. doi: 10.1155/2018/8421394. eCollection 2018.
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.
软骨对于软骨内骨化的骨骼发育至关重要。组织中唯一的细胞类型——软骨细胞，负责产生细胞外基质（ECM）的大分子。在蛋白质和蛋白聚糖被分泌之前，它们在内质网（ER）中经历翻译后修饰和折叠。然而，软骨细胞中的 ER 折叠能力必须与能量和氧水平等生理参数相平衡。特定的细胞条件，例如高蛋白质需求，或病理情况会破坏 ER 稳态并导致折叠不良或错误折叠的蛋白质积累。这种状态称为 ER 应激，并诱导细胞质量控制系统，即未折叠蛋白反应（UPR），以恢复稳态。具有 ER 应激的软骨细胞的不同小鼠模型表现出相似的骨骼表型，代表软骨发育不良。因此，ER 应激本身似乎参与了这些疾病的发病机制。值得注意的是，具有相似表型的软骨发育不良独立于 ER 应激的来源而出现，这些来源如下：（1）导致聚集的 ECM 蛋白突变，（2）内质网伴侣缺陷，（3）UPR 信号因子突变，或（4）聚集蛋白降解缺陷。在任何情况下，由此产生的 UPR 都会严重损害 ECM 蛋白合成、软骨细胞增殖和/或分化或自噬和细胞凋亡的调节。值得注意的是，无论单个或多个事件受到影响，都会出现软骨发育不良。我们分析了软骨特异性 ERp57 敲除小鼠，并证明这种单一的蛋白质二硫键异构酶的缺乏足以诱导 ER 应激并导致 ER 应激相关的骨骼表型，该酶负责 ECM 糖蛋白中二硫键的形成。因此，这些小鼠足以成为分析软骨细胞中 ER 应激的新型模型。它们为 ER 应激相关的身材矮小障碍提供了新的见解，并使分析其他软骨疾病（如骨关节炎）中的 ER 应激成为可能。
