title: 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.
authors.affiliation: Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Stomatology, Central Hospital of Taian, Taian, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China lihuang76@nju.edu.cn.
authors.forename: H
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D002356:Cartilage / Q000473:pathology / Q000502:physiology*; D019902:Chondrocytes / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D008297:Male; D008334:Mandible / Q000502:physiology; D046529:Microscopy, Electron, Transmission; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D002118:Calcium
keywords: 2-aminoethoxydiphenyl borate; apoptosis; chondrocytes; degradation; mandibular condylar; ryanodine