Function of ERp57 in the development and progression of osteoarthritis in the knee joint

• Applicant: Privatdozentin Dr. Rita Dreier
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402797071

Osteoarthritis (OA) is the most common joint disease of adults worldwide. It is characterized by degeneration of the articular cartilage. OA usually occurs in the elderly, but in the course of skeletal dysplasia (e.g. Stickler syndrome, pseudoachondrodysplasia, or multiple epiphyseal dysplasia) young people are also affected by OA. These diseases are triggered by mutations in genes for cartilage components, which usually lead to failure in folding processes occurring in the endoplasmic reticulum (ER). The misfolded cartilage components are not sufficiently secreted and accumulate in the ER. This leads to ER-stress, which initiates the so-called "unfolded protein response" (UPR). At low ER stress, the UPR inhibits translation processes, activates signaling pathways that lead to enhanced synthesis of additional chaperones and protein disulfide isomerases, and initiates the degradation of misfolded proteins. The proliferation of chondrocytes also slows down. If the ER-stress is more intense or persists for a longer time, UPR leads to the programmed cell death by apoptosis. In cartilage, however, ER-stress and the resulting UPR are not only present under pathological conditions but are also part of normal chondrocyte differentiation during enchondral bone formation. The UPR signaling pathways are involved in the regulation of chondrocyte proliferation and apoptosis, which are necessary in bone development and growth. The role of ER-stress during OA is unclear. It could be both, beneficial or the cause of cartilage degeneration. It is also uncertain whether ER stress has opposite effects in early and late phases of the disease. We have established animal and cell culture models in which the protein disulfide isomerase ERp57 is missing in cartilage cells. Using these models, we will analyze the effects of ERp57 loss and the resulting ER stress in cartilage cells. We are interested in compositional changes of the articular cartilage affecting the function of knee joints during OA development and progression. Here, the substrates of ERp57 will be the focus. Furthermore, we plan to characterize the influence of ER stress on the cartilage cell metabolism (vitality, proliferation, differentiation, formation of ECM-degrading proteases) as these properties decisively influence the cartilage function in the joints. In cell cultures, we search for modulators of ER-stress that inhibit cartilage degradation in osteoarthritis. To transfer the results to human osteoarthritis, tissues and isolated chondrocytes from patients with primary osteoarthritis are examined for ER stress and its effects. The results of this project will explain the role of ERp57 and ER stress in cartilage under normal conditions and during OA. In the long term, these findings will open new therapeutic options for the treatment of cartilage degeneration.

• DFG Programme: Research Grants