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.
Highlights
The ability of cells to detect, respond to and survive various stresses is essential for maintaining normal tissue homeostasis
Elevated Endoplasmic reticulum (ER) stress and activation of a resulting unfolded protein response (UPR) is increasingly recognised as a common feature of a number of connective tissue disorders including various forms of chondrodysplasias [5, 29]
In the case of metaphyseal chondrodysplasia type Schmid (MCDS) has the direct role of classical ER stress and the resulting UPR been highlighted through studying the effects induced by the targeted expression of Tgcog in hypertrophic chondrocytes which replicated the disease phenotype (ColXTgcog mouse; 23)
Summary
The ability of cells to detect, respond to and survive various stresses is essential for maintaining normal tissue homeostasis. Failure to maintain homeostasis can result in compromised cell function and disease. The UPR functions to attenuate protein translation thereby reducing the load of nascent proteins arriving at the ER, to up-regulate genes involved in ER associated degradation (ERAD) and to up-regulate chaperones, such as BiP (Grp 78) to increase the protein folding capacity of the ER. The classical UPR is mediated through three ER resident transmembrane proteins which enable the cell to sense increasing levels of ER stress: the basic leucine zipper pancreatic ER kinase (PKR)-like ER kinase (PERK); activating transcription factor 6 (ATF6); and inositol-requiring enzyme 1 (IRE1) [1,2,3,4,5]. All three components of the UPR are proposed to be maintained in an inactive state through association with the abundant luminal chaperone BiP (Grp 78)
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