Pseudoachondroplasia/COMP — translating from the bench to the bedside

• Review of mutant COMP/pseudoachondroplasia (PSACH) mouse models.
• Inducible D469del-COMP mouse mimics all of the PSACH pathology.
• Intracellular retention of mutant COMP is key to PSACH chondrocyte phenotype.
• CHOP and ER stress are central players in the PSACH chondrocyte pathology.
• Inflammation, oxidative and ER stress are activated and are therapeutic targets.

Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.