Active UCHL1 and a DUB trio signature as prognostic biomarkers for early detection, severity assessment, and targeted therapy in traumatic osteoarthritis

Importance Osteoarthritis (OA) is a common and debilitating disease that leads to chronic joint pain and stiffness, making it the leading cause of disability worldwide. In the UK alone, OA affects over 10 million people, significantly impairing their ability to work, participate in daily activities, and enjoy life. This often results in social isolation and a reduced quality of life. Additionally, OA is frequently associated with other chronic conditions such as heart disease and diabetes, complicating treatment and further increasing healthcare costs. Unfortunately, OA is often detected at a late stage when severe joint damage has already occurred, and knee replacement surgery becomes the only effective treatment option. There is an urgent need for earlier detection of OA and the development of tailored therapies that target the disease's root causes before extensive joint damage occurs. Background OA is triggered by mechanical injury to joint cartilage, leading to pain and inflammation. If the tissue does not heal properly, this initial injury can result in ongoing inflammation, tissue damage, and loss of joint function. Recently, we discovered that specific changes occur in joint cells following injury, including the addition or removal of protein markers known as ubiquitin molecules. These changes can promote chronic inflammation and exacerbate tissue damage. Our research has found that enzymes responsible for removing these ubiquitin markers are highly active in injured and osteoarthritic cartilage. These "ubiquitin removers" appear to drive the chronic inflammation and tissue damage seen in OA, suggesting they could serve as key indicators of early disease and potential targets for therapy. Research goal The ultimate goal of this research is to enable early detection of OA and to develop targeted treatments by identifying specific biological early markers, particularly the ubiquitin-removing enzymes that contribute to tissue damage and inflammation. Key objectives To screen for the activity of a signature of four active ubiquitin-removing enzymes in patients' blood plasma and joint fluid to establish them as early markers of OA. To halt cartilage damage by targeting the activity of these enzymes using existing drug compounds in model of OA. Work plan and impact This research has the potential to transform how OA is detected and treated by focusing on early biomarkers and the development of personalised therapies. We will profile the activity of ubiquitin-removing enzymes in the plasma and joint fluid of OA patients as early biomarkers for the disease. Using advanced technologies of spatial transcriptomics which is a method for assigning cell types (identified by the mRNA readouts) to their locations in the patient cartilage histology sections, we will detect the disease profile of each patient. Furthermore, we will study how targeting these enzymes with preexisting drugs inhibitors could delay tissue damage and OA progression in disease models. This comprehensive approach aims to establish a panel of enzymes as early indicators of disease initiation and progression and will further facilitate pre-clinical and clinical trials for targeted therapies, in collaboration with academic researchers, pharmaceutical companies, and clinicians.