Serine proteinases and their inhibitors in cartilage biology and disease
Serine proteinases have a wide range of essential physiological roles including blood clotting, digestion and fertility. However, uncontrolled activity can give rise to disease initiation and perpetuation. My interests lie with their function in cartilage breakdown, a central aetiology in arthritic disease. The key effector proteinases in cartilage destruction are the matrix metalloproteinases (MMPs) but targeting this class of enzymes therapeutically is particularly challenging. No proteinase acts in isolation and increasing evidence supports that both serine and metalloproteinases exist in complex proteolytic networks which results in the observed cartilage destruction in arthritis.
Serine proteinase activity is finely tuned by inhibitors, the largest family of which are the serpins. These inhibitors are highly regulated in osteoarthritis (OA) suggesting an imbalance in homeostasis of the extracellular matrix, resulting in cartilage destruction. Recent work has focused on establishing which serpins are regulated in diseased cartilage and identifying the serine proteinase(s) they target in this tissue. A better understanding of how serine proteinases are regulated by their endogenous inhibitors in cartilage, and how this changes in disease will ultimately lead to new avenues to explore for therapeutic intervention. An overview of the role of serine proteinases in arthritis
The importance of proteinase inhibitors in skeletal development
This research focuses on the differentiation of human mesenchymal stem cells (hMSCs) into cartilage (chondrogenesis) and to a lesser extent, bone (osteogenesis). We have demonstrated that serine proteinases inhibitors (serpins) have a functional role in pushing stem cells down particular cellular lineages. Current work focuses on understanding the mechanism(s) behind this, and how this can translate into improving the function of cartilage which can be engineered in vitro.
Using activity-based probes to capture active proteinases in the OA joint: new insights into active disease mechanisms
March 2022 - March 2023