The wrong place at the wrong time: Immune cell-derived serine proteases as drivers of osteoarthritis

About the Project

This project combines cutting-edge with established methods including activity-based probes, protein biology, ex vivo explant culture, ‘omic data analysis and in vivo models to reveal how serine proteases activate destructive MMP pathways. You’ll gain multidisciplinary skills across biochemistry, imaging and translational science seeking to tackle a major unmet clinical challenge and helping to identify new therapeutic targets to protect joints from destruction in arthritis.

Osteoarthritis (OA) is a progressive, debilitating joint disease in which excessive proteolytic activity drives irreversible cartilage breakdown. While matrix metalloproteinases (MMPs) are key mediators of this process, the upstream mechanisms controlling their activation remain poorly understood. Emerging evidence suggests that serine proteinases act as critical physiological activators of pro-MMPs (Wilkinson et al., 2019).

Although defined by cartilage degradation, OA is a disease of the whole joint, with the inflamed synovium playing a central role in shaping the joint microenvironment. Serine proteinases released by infiltrating and resident immune cells may initiate or amplify MMP activation. We have recently demonstrated such a role for neutrophil elastase (Wilkinson et al., 2022), but other immune cell types (e.g. macrophages, mast cells) are also likely contributors, and their roles remain largely unexplored.

This exciting three-year PhD project will uncover how immune cell–derived serine proteinases drive MMP activation and cartilage destruction in OA. The project integrates human tissue analysis, state-of-the-art activity-based probes, and in vivo models to define protease activity throughout the disease course.

Aim 1: Characterise immune cell–derived serine proteinases in OA synovium using immunohistochemistry and single-cell RNA sequencing datasets (e.g. Huang et al., 2022).

Aim 2: Define how these proteinases activate proMMPs and drive cartilage destruction using biochemical assays, mass spectrometry and human cartilage explant models (Wilkinson et al., 2017a,b).

Aim 3: Visualise immune protease activity in vivo using novel activity-based probes in experimental OA models (Wilkinson et al., 2026).

This project will deliver new insight into immune-driven protease networks in OA and identify novel therapeutic targets to slow or prevent cartilage degradation.

Based at the University of Liverpool under the supervision of Dr David Wilkinson. You will join an inclusive, supportive and engaging research environment, gaining a broad, multidisciplinary skillset spanning protein biochemistry, imaging, and translational musculoskeletal research. This project is well-suited to an ambitious bioscience or clinical graduate with an interest in early target discovery research.