Increased Classical Endoplasmic Reticulum Stress Is Sufficient to Reduce Chondrocyte Proliferation Rate in the Growth Plate and Decrease Bone Growth

Abstract

Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2α and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole.

Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis

“…The ER stress system is typically activated in response to stressors, including excessive amounts of unfolded proteins in the ER. ER stress response in PD was recently reported (Domon et al, 2009;Kung et al, 2015;Yamada et al, 2015). These authors suggested that modulation of the ER stress system could have therapeutic effects.…”

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

“…During development, however, it also negatively impacts chondrocyte proliferation and the longitudinal growth of long bones, independently of ECM abnormalities [38]. The Dmm/+ mouse displays UPR activation in articular chondrocytes prior to the onset of OA [28].…”

New developments in chondrocyte ER-stress and related diseases

“…Interestingly, BiP expression was markedly increased after DMM surgery in wild-type mice, clearly demonstrating an involvement of ER stress and the UPR in the pathogenesis of OA. However, whilst BiP levels were also increased upon DMM surgery in the transgenic mice overexpressing a misfolding variant of thyroglobulin (Tg cog ) under the Col2a1 promoter (ColIITg cog , a model of cartilage-specific ER stress 51 ), the onset of OA was delayed, and a delay in cartilage apoptosis and damage was seen two weeks after surgery compared with wild-type controls. Interestingly, ColIITg cog mice had elevated BiP protein levels prior to DMM surgery, and the prosurvival Xbp1-associated UPR signalling network was activated in ColIITg cog mice after DMM, suggesting that pre-exposure to ER stress or activation of the specific pro-survival UPR responses such as the Xbp1s signalling could be chondroprotective.…”