| Popis: |
The burden of osteoarthritis continuous to increase. While joint replacement surgery provides a cost effective and efficacious treatment for end stage osteoarthritis, no treatment exists to prevent or slow the progression of the disease. Understanding the cellular and molecular changes in the synovium following trauma and in early osteoarthritis could facilitate the identification of novel therapeutic targets. Previous studies identified synovial hyperplasia following intra-articular fractures, cartilage injury and in osteoarthritis. In mice, proliferation of synovial mesenchymal stromal/stem cells (MSCs) leads to synovial hyperplasia following joint surface injury. The driver for this expansion of MSCs in the synovium is unknown. Recently, YAP, a key downstream effector of the Hippo pathway, has been shown to causes tissue overgrowth due to modulation of MSC proliferation. The joint surface injury model of osteoarthritis was used to investigate whether YAP may play a role in synovial hyperplasia following joint surface injury. This work shows that synovial hyperplasia is common to both healer and non-healer mouse strains after joint injury and that Yap expression is up regulated on a protein and mRNA level. Using the same injury model in a mouse with a conditional knockout of Yap in Gdf5 lineage cells, showed that a Yap knockout in Gdf5 progeny cells prevented hyperplasia of synovial lining after joint surface injury, suggesting that YAP is required for MSCs in the synovium to proliferate. In patient synovial samples, YAP expression was up regulated in activated synovium, including a subset of CD55 positive fibroblast-like synoviocytes in the synovial lining. Proliferating cells were positive for active YAP. This suggests that findings in our mouse model are clinically relevant. Furthermore, modulation of YAP and synovial MSC proliferation after JSI provides a means to study the role of synovial hyperplasia after trauma. This could lead to a potential novel therapeutic target for the treatment of posttraumatic osteoarthritis. |
