Ca²⁺-Dependent Endoplasmic Reticulum Stress Regulates Mechanical Stress–Mediated Cartilage Thinning

Abstract

Our previous study identified that endoplasmic reticulum stress (ERS) plays a critical role in chondrocyte apoptosis and mandibular cartilage thinning in response to compressive mechanical force, although the underlying mechanisms remain elusive. Because the endoplasmic reticulum (ER) is a primary site of intracellular Ca(2+) storage, we hypothesized that Ca(2+)-dependent ERS might be involved in mechanical stress-mediated mandibular cartilage thinning. In this study, we used in vitro and in vivo models to determine Ca(2+) concentrations, histological changes, subcellular changes, apoptosis, and the expression of ERS markers in mandibular cartilage and chondrocytes. The results showed that in chondrocytes, cytosolic Ca(2+) ([Ca(2+)]i) was dramatically increased by compressive mechanical force. Interestingly, the inhibition of Ca(2+) channels by ryanodine and 2-aminoethoxydiphenyl borate, inhibitors of ryanodine receptors and inositol trisphosphate receptors, respectively, partially rescued mechanical force-mediated mandibular cartilage thinning. Furthermore, chondrocyte apoptosis was also compromised by inhibiting the increase in [Ca(2+)]i that occurred in response to compressive mechanical force. Mechanistically, the ERS induced by compressive mechanical force was also repressed by [Ca(2+)]i inhibition, as demonstrated by a decrease in the expression of the ER stress markers 78 kDa glucose-regulated protein (GRP78) and 94 kDa glucose-regulated protein (GRP94) at both the mRNA and protein levels. Collectively, these data identified [Ca(2+)]i as a critical mediator of the pathological changes that occur in mandibular cartilage under compressive mechanical force and shed light on the treatment of mechanical stress-mediated cartilage degradation.

Endoplasmic reticulum stress remodels alveolar bone formation after tooth extraction

“…ER stress induced by alcohol and periodontitis can lead to apoptosis of osteoblasts and bone resorption 19,20 . In vivo experiments have shown that ER stress plays a critical role in chondrocyte apoptosis and mandibular cartilage thinning in response to compressive mechanical force, which could lead to apoptosis 21,22 . The effect of ER stress may be influenced by different routes of inducement and duration, resulting in differences in the inhibition or promotion of osteogenesis.…”

PI3‐kinase/Akt pathway‐regulated membrane transportation of acid‐sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF‐induced HSC Activation

“…The endoplasmic reticulum (ER) is a complex and key organelle for protein folding, and lipid and carbohydrate metabolism . It is also an important Ca 2+ storage station that regulates intracellular Ca 2+ signalling that affects many signalling pathways . Intracellular calcium disorders affect ER functions including protein synthesis, folding and translation, which triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) .…”

BIO alleviated compressive mechanical force‐mediated mandibular cartilage pathological changes through Wnt/β‐catenin signaling activation

“…S‐1). The rats in force groups wore the appliance for 4 or 7 d. After 24 or 96 h of loading, all of the anesthetized rats were given injections of BIO (10 μl of 1 μM solution) into the articular capsules of the condyle on one side and vehicle (10 μl) on the other side . All of the animals were sacrificed at the fourth or seventh day (refer to Fig.…”