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.

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

“…Therefore, it was apparent that the lack of matrilin‐3 in the cartilage ECM in itself did not cause EDM5. In fact, later studies by Nundlall et al reported that the retention of mutant matrilin‐3 within the ER lumen induces a pathological ER stress and the UPR (Reviewed in Briggs et al 2020) 46,50 . This in turn, has detrimental consequences on chondrocyte phenotype (including decreased proliferation and increased cell death) and subsequently on endochondral ossification and long bone growth.…”

The Induced Pluripotent Stem Cells in Articular Cartilage Regeneration and Disease Modelling: Are We Ready for Their Clinical Use?

“…Another group of disorders related to chondrogenesis that was studied using iPSC modelling is connected with the accumulation of proteins in the intracellular compartments of chondrocytes, leading to the activation of the unfolded protein response (UPR) [171,172,182]. Among them, we may distinguish multiple epiphyseal dysplasia (MED) and metaphyseal chondrodysplasia type Schmid (MCDS), which are related to the widening and irregularity of growth plates, an increased risk of developing early osteoarthritis of the knee and hip [171,183,184].…”

“Lessons from Rare Forms of Osteoarthritis”

“…Research on chondrodysplasias has also revealed the potential role of endoplasmic reticulum stress (ER stress) as a disease mechanism not only in the pathogenesis of rare cartilage syndromes but potentially in common OA [50]. ER stress occurs when the ability of the endoplasmic reticulum to fold proteins is defective, leading to impaired cell function and if severe enough, to cell death.…”