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Updated: Jul 28, 2026
Matrix-assisted Autologous Chondrocyte Transplantation for Remodeling and Repair of Chondral Defects in a Rabbit Model
Published on: May 21, 2013
Selective intracellular retention of extracellular matrix proteins and chaperones associated with
Insights
Mutations in the cartilage oligomeric matrix protein (COMP) gene cause pseudoachondroplasia (PSACH). This study identifies a novel COMP mutation leading to abnormal protein retention and altered extracellular matrix in chondrocytes.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Pseudoachondroplasia (PSACH) is a genetic chondrodysplasia caused by mutations in the cartilage oligomeric matrix protein (COMP) gene.
- COMP is a crucial secreted glycoprotein in cartilage extracellular matrix, essential for skeletal development.
- PSACH is characterized by short stature and early-onset osteoarthritis.
Purpose of the Study:
- To identify and characterize a novel mutation in the COMP gene associated with PSACH.
- To investigate the cellular mechanisms underlying the retention of mutant COMP and its impact on chondrocyte function.
- To explore the role of molecular chaperones in the intracellular trafficking of mutant COMP.
Main Methods:
- Genetic analysis to identify a novel missense mutation in the COMP gene (G to D substitution in the TSP type 3 calcium-binding domain).
- Immunohistochemistry and immunoelectron microscopy to examine COMP localization and identify co-retained proteins within chondrocytes.
- Analysis of the expression and localization of molecular chaperones (HSP47, PDI, calnexin) in affected chondrocytes.
Main Results:
- A novel missense mutation in the COMP gene was identified in a patient with PSACH.
- Abnormal retention of mutant COMP was observed within enlarged endoplasmic reticulum (rER) inclusions in PSACH chondrocytes.
- Selective co-retention of fibromodulin, decorin, collagens IX, XI, and XII, and molecular chaperones (HSP47, PDI, calnexin) within the rER was demonstrated.
- Aggrecan and collagens II and VI were not retained intracellularly.
Conclusions:
- The identified COMP mutation leads to intracellular retention of the mutant protein within chondrocytes.
- Mutant COMP retention causes selective co-trafficking and retention of specific extracellular matrix components and molecular chaperones.
- These findings suggest distinct ER-sorting mechanisms or secretory pathways for matrix molecules, potentially mediated by chaperone interactions.
Abstract:
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 have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.
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