Ten million UK adults with osteoarthritis have no drug that stops their joints from breaking down—only painkillers and surgery. This project targets a newly identified culprit: an enzyme called COLGALT2, found in abnormally high levels in the cartilage cells of people genetically prone to the disease. The problem is that no one knows exactly what COLGALT2 does in cartilage, or how its excess leads to joint degeneration. The researchers will answer three questions: whether too much COLGALT2 weakens collagen fibres, whether it alters how joints form in the womb, and whether existing drugs can safely reduce its activity. If successful, this work could open the door to the first disease-modifying drug for osteoarthritis—a pill that slows or prevents cartilage loss, rather than just managing symptoms. That would spare millions from joint replacement surgery, which is expensive, risky, and not always effective. The project is fundamental biology: understanding how a single enzyme drives a common disease. But that mechanistic knowledge is the missing link between genetic risk and a real treatment.
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Osteoarthritis is the most common arthritis, and a leading cause of disability globally. This debilitating disease is characterised by the breakdown of cartilage in synovial joints. In a healthy joint, cartilage is a smooth tissue that covers the ends of the bones, allowing friction free movement. Cartilage is a dense matrix consisting of large collagen fibres produced by a specialised cell type, chondrocytes. Collagens are a vital component of cartilage, providing structural integrity to the tissue and allowing it to withstand mechanical load. In osteoarthritis, the matrix irreversibly degenerates, leading to chronic pain and stiffness in the affected joints, co-morbidities, disability, and premature death. In the UK alone, 10 million adults suffer with osteoarthritis, yet treatments are limited to pain relief, physiotherapy, and joint replacement surgery (arthroplasty), which is expensive and risk-laden, with variable success rates. Our recent studies of human DNA and patient cells has identified that a subset of adults who are at higher genetic risk of developing osteoarthritis produce greater amounts of COLGALT2, specifically in chondrocytes. COLGALT2 is an enzyme capable of glycosylating collagens, a process of transferring sugars to the protein surface. This is essential for collagen structure and function. We have further identified that these elevated levels are present from the beginning of life (during development of the skeleton), indicating individuals are “pre-programmed” to develop osteoarthritis, ostensibly due to conferred weaknesses to the cartilage. To date, this enzyme remains largely uncharacterised, and its biological role in joint disease is unknown. This proposed research will utilise three interlinked yet independent innovative approaches to understand the biology of COLGALT2 in cartilage and how this contributes to osteoarthritis pathogenesis. We will primarily answer three key questions: Do COLGALT2 levels in mature chondrocytes directly impact collagen glycosylation, impacting fibril assembly and stability, contributing to disease? Do COLGALT2 levels impact the development of the joint, shape or tissue composition, predisposing individuals to disease? Can drug repurposing allow us to modulate COLGALT2 in chondrocytes and be applied as a health intervention? In Newcastle, we will first culture human primary chondrocytes, isolated from osteoarthritis samples post-arthroplasty. Applying established molecular technologies, we will modulate COLGALT2 levels and quantify the impact upon both the chondrocyte proteome and the matrix composition using a range of cell biology and 3D culture methods. To ensure the success of this work, we will draw upon the vast expertise of our global network of leading scientific collaborators. In Bristol, we will use in vivo technologies to complement and validate these findings in zebrafish. Zebrafish provide an excellent model of the skeletal system. Many skeletal structures are shared with humans and can be easily visualised in the translucent fish. This is enhanced by our ability to fluorescently label specific musculoskeletal cell types. Finally, we will conduct a high-throughput screen of approved drugs to identify pharmacological modulators of COLGALT2. We will then transfer this knowledge to the Newcastle and Bristol laboratories, to validate the results in our optimised in vitro and in vivo models, respectively. Understanding the fundamental biology underlying disease will bridge the gap between genetic studies and targeted therapies for osteoarthritis patients. This research has the potential to benefit millions of adults in the UK. The development of drug treatments for osteoarthritis would confer a long-term benefit at both an individual and societal level.
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