# From Protein Misfolding to Extracellular Matrix Disorganisation: Understanding Disease Pathology in Rare Skeletal Dysplasias

## TL;DR

This paper reviews how protein misfolding in rare skeletal disorders leads to ECM disruption, affecting joint health and growth.

## Contribution

The paper provides a comprehensive review of shared pathogenic mechanisms in PSACH and MED, emphasizing ECM disorganization as a central factor.

## Key findings

- Mutant ECM proteins cause ER stress in chondrocytes, impairing cell function.
- Secreted mutant proteins disrupt collagen and proteoglycan organization in the ECM.
- ECM abnormalities affect tendons, ligaments, and muscles, contributing to joint and muscle issues.

## Abstract

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are rare, autosomal dominant skeletal dysplasias characterised by disproportionate short stature, joint deformities, and early-onset osteoarthritis. These conditions result from mutations in key cartilage extracellular matrix (ECM) components, including cartilage oligomeric matrix protein (COMP), matrilin-3, and type IX collagen. Although genetically and clinically heterogeneous, PSACH and MED share convergent pathogenic mechanisms. Misfolded mutant ECM proteins are retained within the endoplasmic reticulum (ER) of growth plate chondrocytes, triggering chronic ER stress and impairing chondrocyte proliferation, differentiation, and survival. Moreover, some of the mutant protein is secreted and incorporated into the matrix, leading to altered collagen fibrillogenesis, disrupted proteoglycan distribution, and compromised biomechanical integrity. These alterations extend beyond cartilage, impacting tendons, ligaments, and muscle–tendon junctions, contributing to joint laxity, impaired force transmission, and mild myopathy. This review discusses the structural and functional consequences of ECM disorganisation in PSACH and MED, highlighting its central role in disease progression and emphasising the importance of considering ECM abnormalities when developing therapeutic strategies for rare short stature-associated skeletal disorders.