Aggrecan, the large aggregating chondroitin sulfate proteoglycan of cartilage, is the critical component of the cartilage extracellular matrix (ECM) that causes the expansion of cartilage tissue volume and enables articular cartilage to withstand compression and protect the bony surfaces of joints. The progression of osteoarthritic and other skeletal diseases is characterized by the loss of aggrecan, deterioration of cartilage ECM structure and function, and a failure to properly repair damaged cartilage tissue. The long-term goal is to understand interrelationships between ECM precursors and the cellular processing and trafficking machinery in chondrocytes involved in the formation of a normal ECM, and the alterations that underlie skeletal disease. Studies are based on the premise that critical synthetic and processing events occur in specific intracellular compartments prior to secretion, and under some circumstances are tailored to the unique requirements of specialized cells, exemplified in this case by the balanced production of aggrecan in the chondrocyte. We hypothesize that the Chondrocyte Aggrecan Precursor-containing (late) ER compartment we discovered in chondrocytes, CAP-ER, functions specifically as a gatekeeper for aggrecan quality control.
The specific aims are to 1) determine the features that define CAP-ER as a unique compartment utilized specifically in chondrocytes and 2) elucidate the dynamics of CAP-ER utilization in the post-translational regulation of aggrecan processing, trafficking and quality control. CAP-ER will be isolated by subcellular fractionation and characterized, and its biological function will be addressed in dynamic studies using live cell imaging of aggrecan-GFP proteins. These studies offer new possibilities for understanding a novel posttranslational mechanism for regulating a key molecule essential to the stability and normal function of cartilage, and will provide a new perspective on dysregulation in skeletal diseases such as osteoarthritis. Understanding the normal processes in maintaining and regulating the structure composition of cartilage, and hence its function, will set a basis for future medical intervention and improved health. ? ? ?
| Venditti, Rossella; Scanu, Tiziana; Santoro, Michele et al. (2012) Sedlin controls the ER export of procollagen by regulating the Sar1 cycle. Science 337:1668-72 |
| Chen, Tung-Ling L; Posey, Karen L; Hecht, Jacqueline T et al. (2008) COMP mutations: domain-dependent relationship between abnormal chondrocyte trafficking and clinical PSACH and MED phenotypes. J Cell Biochem 103:778-87 |
