Chondrodysplasias are a group of genetic disorders that affect the development and growth of cartilage. These disorders can result in extreme short stature, craniofacial defects, joint malformation, and early osteoarthritis; severely impacting quality of life for affected individuals. Many chondrodysplasias are caused by mutations in genes encoding cartilage extracellular matrix (ECM) proteins. These mutations typically result in synthesis of abnormal proteins that are improperly folded, and hence inappropriately retained within the endoplasmic reticulum (ER) of the cell, activating ER stress and the unfolded protein response (UPR), an adaptive cellular response to minimize production of the mutant protein and/or to enhance protein folding, degradation or export. If prolonged, activation of the UPR causes apoptotic cell death. Many human disorders have an underlying mechanism in UPR activation, and targeting ER stress pathways is showing promise for development of therapeutics for these conditions. Understanding and modeling the UPR in chondrodysplasia will be essential to advance such targeted approaches for the benefit of chondrodysplasia patients. The focus of this review is to compare the mechanistic sequelae of ECM protein mutations in chondrodysplasia that may cause chondrocyte ER stress and UPR activation, and to present current and future directions in chondrodysplasia disease modeling and therapeutic intervention.
Keywords: extracellular matrix (ECM) mutations; genetic cartilage disorders; human dwarfism; iPSC models; unfolded protein response (UPR).
© 2014 Wiley Periodicals, Inc.