New developments in chondrocyte ER stress and related diseases

Abstract

Cartilage comprises a single cell type, the chondrocyte, embedded in a highly complex extracellular matrix. Disruption to the cartilage growth plate leads to reduced bone growth and results in a clinically diverse group of conditions known as genetic skeletal diseases (GSDs). Similarly, long-term degradation of articular cartilage can lead to osteoarthritis (OA), a disease characterised by joint pain and stiffness. As professionally secreting cells, chondrocytes are particularly susceptible to endoplasmic reticulum (ER) stress and this has been identified as a core disease mechanism in a group of clinically and pathologically related GSDs. If unresolved, ER stress can lead to chondrocyte cell death. Recent interest has focused on ER stress as a druggable target for GSDs and this has led to the first clinical trial for a GSD by repurposing an antiepileptic drug. Interestingly, ER stress markers have also been associated with OA in multiple cell and animal models and there is increasing interest in it as a possible therapeutic target for treatment. In summary, chondrocyte ER stress has been identified as a core disease mechanism in GSDs and as a contributory factor in OA. Thus, chondrocyte ER stress is a unifying factor for both common and rare cartilage-related diseases and holds promise as a novel therapeutic target.

Keywords: cartilage; chondrocyte; drug repurposing; endoplasmic reticulum; osteoarthritis; skeletal dysplasia.

Figure 1.. The unfolded protein response (UPR) is activated by ER stress and works through three distinct pathways.

The accumulation of misfolded proteins within the endoplasmic reticulum (ER) lumen initiates the UPR. Misfolded proteins are recognised by binding immunoglobulin protein (BiP), which dissociates from three transmembrane-bound receptors—protein kinase ribonucleic acid-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE-1) and activating transcription factor 6 (ATF6)—and binds to the exposed hydrophobic residues on the unfolded protein. Following BiP dissociation from PERK, it homodimerises, leading to autophosphorylation. PERK phosphorylates and inactivates the alpha subunit of eukaryotic translation initiation factor 2A (eIF2α) required for mRNA 5′ capping and 80s ribosomal activity. This leads to the reduction of global protein synthesis, thus reducing the load on the ER. BiP dissociation from the luminal domain of IRE-1α leads to homodimerisation and activation of its ribonuclease activity. Active IRE-1 cleaves a 26-nucleotide intron sequence from unspliced XBP1 (XBP1u) messenger RNA, resulting in the translation of spliced XBP1 (XBP1s). Spliced XBP1 functions as a transcription factor and migrates to the nucleus, where it binds the promoters and up-regulates genes encoding chaperones, protein disulphide-isomerases (PDIs) and genes encoding the proteins of ER-associated protein degradation. ATF6 consists of an ER luminal domain that binds BIP and a cytoplasmic domain of a bZip transcription factor. Dissociation of BiP from ATF6 allows for interactions between ATF6 and the COPII vesicular complex. ATF6 translocates to the Golgi apparatus, where it undergoes cleavage by site 1 and site 2 proteases. Following cleavage, the cytosolic portion of ATF6 acts as a transcription factor, binding to the promoters of target genes encoding chaperones and genes involved in ER-associated protein degradation and apoptosis. Therefore, these three signalling pathways are activated with the ultimate aims of ceasing translation, degrading the misfolded protein and (if the stress cannot be overcome) promoting cell death.