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

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 ca2+ storage,we hypothesized that ca2+-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 ca2+ concentrations,histological changes,subcellular changes,apoptosis,and the expression of ers markers in mandibular cartilage and chondrocytes. the results showed that in chondrocytes,cytosolic ca2+ ([ca2+]i) was dramatically increased by compressive mechanical force. interestingly,the inhibition of ca2+ 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 [ca2+]i that occurred in response to compressive mechanical force. mechanistically,the ers induced by compressive mechanical force was also repressed by [ca2+]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 [ca2+]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. © international & american associations for dental research.