Our research programme focuses on understanding the molecular pathogenesis of chronic degenerative diseases such as arthritis, with the goal of developing novel therapies to treat these conditions. We focus specifically on defining how the activity and availability of anabolic growth factors and metalloprotease inhibitors is regulated by their trafficking between pericellular heparan sulfate proteoglycans and the cell surface endocytic receptor LRP1. 

​(i) Heparan sulfate proteoglycans regulate cellular responses in health and disease.

Heparan sulfate proteoglycans bind >500 proteins (including cytokines and growth factors), and regulate their localisation, stability, and signaling. We are interested in how dynamic changes in heparan sulfate structure alter cellular responses to external stimuli, both in health and in diseases like osteoarthritis, rheumatoid arthritis, and age-related macular degeneration.

e.g. We showed that specific heparan sulfate patterns promote type I interferon signaling in macrophages and exacerbate inflammatory arthritis.  

​(ii) Recycling of heparan sulfate ligands via the scavenger receptor LRP1

Many proteins that interact with heparan sulfate proteoglycans can be cleared from the extracellular environment by the scavenger receptor, LDL receptor-related protein 1 (LRP1). We are investigating molecular determinants that balance this equilibrium and how it becomes disrupted in chronic degenerative diseases.

e.g. Altered heparan sulfate structure in osteoarthritic cartilage correlates with loss of the protective metalloprotease inhibitor TIMP-3 via LRP1, accelerating joint damage.