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We research what increases and decreases loss of cartilage in osteoarthritis, to improve treatment solutions for the condition.

Targeting excess metalloprotease activity in osteoarthritis

Osteoarthritis 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 increase in metalloprotease activity is caused both by an increase in expression of the metalloproteinases and by a decreased level of their endogenous inhibitor, tissue inhibitors 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).

We are currently investigating how HS sulfation patterns change in OA, and whether we can target this extracellular trafficking pathway to inhibit osteoarthritic cartilage loss.

Regulation of 'sheddase' activity

We discovered that the same pathway that regulates TIMP-3 in chondrocytes also acts in macrophages, where TIMP-3 is the primary inhibitor of TNF release by the metalloproteinase ADAM17.

We are currently investigating how this pathway regulates the acute inflammatory response, and whether it is disrupted in chronic inflammatory conditions.

Our team