Novel therapeutic interventions for pseudoachondroplasia.

Pseudoachondroplasia (PSACH), a severe short-limbed dwarfing condition, is associated with life-long joint pain and early onset osteoarthritis. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric matricellular protein expressed primarily in cartilage and other musculoskeletal tissues. Mutations in COMP diminish calcium binding and as a result perturb protein folding and export to the extracellular matrix. Mutant COMP is retained in the endoplasmic reticulum (ER) of growth plate chondrocytes resulting in massive intracellular COMP retention. COMP trapped in the ER builds an intracellular matrix network that may prevent the normal cellular clearance mechanisms. We have shown that accumulation of intracellular matrix in mutant-COMP (MT-COMP) mice stimulates intense unrelenting ER stress, inflammation and oxidative stress. This cytotoxic stress triggers premature death of growth plate chondrocytes limiting long-bone growth. Here, we review the mutant COMP pathologic mechanisms and anti-inflammatory/antioxidant therapeutic approaches to reduce ER stress. In MT-COMP mice, aspirin and resveratrol both dampen the mutant COMP chondrocyte phenotype by decreasing intracellular accumulation, chondrocyte death and inflammatory marker expression. This reduction in chondrocyte stress translates into an improvement in long-bone growth in the MT-COMP mice. Our efforts now move to translational studies targeted at reducing the clinical consequences of MT-COMP and painful sequelae associated with PSACH.