Academic Background

Research programme

Our research programme is focused on understanding the molecular pathogenesis of chronic degenerative diseases such as osteoarthritis, with the goal of developing novel therapies to treat these conditions. We focus specifically on defining how the 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) Defining molecular pathways that drive cartilage loss in osteoarthritisOsteoarthritis is characterised by an increase in the activity of metalloproteases that degrade cartilage extracellular matrix components, and so impair the structural integrity of the tissue. This is caused by increased expression of these metalloproteases, as well as by a decrease in levels of their endogenous inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3). Our group established that levels of TIMP-3 in cartilage are regulated by the equilibrium between its binding to heparan sulfate (HS) glycans in the extracellular matrix and its cellular endocytosis by the scavenger receptor, LDL receptor-related protein 1 (LRP1). Current projects focus on defining how HS sulfation patterns change in OA, and designing small molecule inhibitors to target TIMP-3 loss as a therapy for osteoarthritis.

(ii) LRP1/HS axis also regulates macrophage behaviourWe found that LRP1 also dynamically regulates TIMP-3 levels in macrophages, where TIMP-3 is the primary inhibitor of TNF release by the metalloproteinase ADAM17. This enables LRP1 to control termination of TNF release during the inflammatory response. As in chondrocytes, macrophage HS protects TIMP-3 and other ligands from uptake by LRP1. We are examining changes in expression of HS biosynthesis enzymes and core proteins upon macrophage phenotype and activation, and looking at how this alters retention and biological activity of HS-binding cytokines, chemokines and growth factors during inflammation. 

View graph of relations

ID: 147476203