Characterization of the Unfolded Protein Response in Chondrocytes
Dr. Julia Oxford
Chondrocytes are cells that are specialized for extremly high levels of biosynthesis and secretion of extracellular matrix proteins. The unfolded protein response (UPR) represents a network of signaling pathways that regulate protein biosynthesis and transport in the rough endoplasmic reticulum (ER). For cells that dedicate a very high level of activity to the production and secretion of extracellular molecules, a deficiency in the secretory pathway may lead to improper folding of proteins within the ER. Mutations affecting the activity of these pathways have been associated with numerous congenital disease states, including those affecting musculoskeletal development such as Laron dwarfism, Osteogenesis imperfecta, Spondyloepiphysial dysplasia, and Wollcott-Rallison syndrome. The Chondrodysplasia (cho/cho) mouse is homozygous for a single nucleotide deletion that results in a frameshift in the gene encoding the alpha chain of collagen XI. The truncated and nonfunctional protein product may obstruct normal ER processing leading to activation of the UPR. Experiments were carried out to detect the truncated protein using antibodies specific for this region. These results were verified by mass spectrometry. Characterization of potential activation of the UPR was investigated to determine if the mutation in Col11a1 induces the UPR, and if the UPR then contributes to the chondrodystrophic phenotype. Investigation of a putative role for UPR activation in the cho/cho mouse provides evidence regarding the hypothesis that chondrodystrophies can be classified among the protein folding diseases. This information serves to inform biomedical research that relies upon this model system to develop therapies addressing developmental disorders of musculoskeletal tissues in humans.