Pseudoachondroplasia is caused through both intra- and extracellular pathogenic pathways.

Pseudoachondroplasia is a dominantly inherited chondrodysplasia associated with mutations in cartilage oligomeric matrix protein (COMP). Investigations into the pathogenesis of pseudoachondroplasia are hampered by its rarity. We developed a cell culture model by expressing mutant COMP in bovine primary chondrocytes using a gutless adenoviral vector. We show that mutant COMP exerts its deleterious effects through both intra- and extracellular pathogenic pathways. Overexpression of mutant COMP led to a dose-dependent decrease in cellular viability. The secretion of mutant COMP was markedly delayed, presumably due to a prolonged association with chaperones in the endoplasmic reticulum (ER). The ECM lacked organized collagen fibers and showed amorphous aggregates formed by mutant COMP. Thus, pseudoachondroplasia appears to be an ER storage disease, most likely caused by improper folding of mutant COMP. The growth failure of affected patients may be explained by an increased cell death of growth-plate chondrocytes. Dominant interference of the mutant protein on collagen fiber assembly could contribute to the observed failure of the ECM of cartilage and tendons.