Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia

Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We hav e identified a novel missense, mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding do main of COMP in a patient diagnosed with PSACH. Immunohistochemistry and im munoelectron microscopy both show abnormal retention of COMP within charact eristically enlarged rER inclusions of PSACH chondrocytes, as well as reten tion of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan a nd types II and VI collagen were not retained intracellularly within the sa me cells. In addition to selective extracellular matrix components, the cha perones HSP47, protein disulfide isomerase (PDI) and calnexin were localize d at elevated levels within the rER vesicles of PSACH chondrocytes, suggest ing that they may play a role in the cellular retention of mutant COMP mole cules. Whether the aberrant rER inclusions in PSACH chondrocytes are a dire ct consequence of chaperone-mediated retention of mutant COMP or are otherw ise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstra te that retention of mutant COMP molecules results in the selective retenti on of ECM molecules and molecular chaperones, indicating the existence of d istinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones. ( C) 2001 Elsevier Science B.V./International Society of Matrix Biology. All rights reserved.