Cartilage Integrity and Osteo-Arthritis controled by c-Fos

Osteoarthritis (OA) is the most common destructive joint disease, that affects 250 million people worldwide. In recent years the traditional view of OA, as a wear and tear condition has been revised and there can be no doubt that the whole joint is involved. OA can be caused by aging, traumatic injury, genetic factors, and inflammatory and metabolic factors. Regardless of the cause, OA is characterized by progressive cartilage loss, synovial inflammation, and bone changes and there is no therapy for the disease. Although alterations in articular chondrocytes, cartilage forming cells and cartilage matrix have been characterized in articular cartilage from OA patients and animal models, the pathological mechanisms that link articular chondrocytes-cartilage matrix alteration and risk factors have barely been investigated. There is convincing evidence that knee OA risk is about 40% heritable, suggesting key roles for articular chondrocytes, genetic factors and cartilage matrix in mediating OA risk. However, how articular chondrocytes control cartilage integrity and respond to environmental factors through genetic factors during OA progression remain elusive. Our preliminary data show that c-Fos/AP-1, a protein has been involved in skeletal development and other diseases, is increased in articular chondrocytes during cartilage degeneration in an experimental OA model. It is likely that c-Fos/AP-1 has unique roles during OA progression through organizing collagen/cartilage matrix structure in the articular cartilage. The goal is to understand the underlying disease mechanisms of OA. A major part of this is identifying early responses of articular chondrocytes, to stress on the knee joint. Combining experimental OA model, comparative transcriptomics, bone morphometric analysis and biophysics, we aim to dissect OA mechanism and discover mechanism- based new therapeutical targets. Limited knowledge of how chondrocytes produce and maintain cartilage matrixes and poor understanding of the molecular mechanisms in the initiation of OA leading to irreversible cartilage loss have hampered early diagnosis and the design of effective therapeutic strategies aimed at preventing it. Identification of molecular events, ideally in very early-stage, that link to cartilage destruction would be a great innovation to enable proper disease management and reduction of the burden of disease. This study will identify a new protective mechanism regulating knee cartilage integrity involving c-Fos and reveal the relationship between physical characteristics of articular cartilage and gene expression during cartilage degeneration. The findings from this project could provide key information to find therapeutically actionable targets that potentiate cartilage integrity for OA patients.