Dr Clare Hughes - PhD
Cartilage Proteoglycan Metabolism in Osteoarthritis
The synovial joint is a complex structure composed of a number of component specialized connective tissues. Research is directed at understanding the mechanisms underlying the pathological changes that occur in the articular cartilage and synovial joint cavity lining during the progression of osteoarthritis. Research in our laboratories has focused on studying the role that the metalloproteinases belonging to the ADAMTS (a disintegrin and metallo with thrombospondin) family (namely ADAMTS4 and ADAMTS5) have in the cleavage of aggrecan a key process in the pathology of osteoarthritis
Articular cartilage chondrocytes are responsible for the synthesis, organization and maintenance of a specialized extracellular matrix composed predominantly of type II collagen fibrils enmeshing large, multimolecular aggregates of cartilage proteoglycan (aggrecan) bound to hyaluronan (HA) and stabilized by cartilage link protein. The entrapment of the large, highly hydrated proteoglycan aggregates within the collagen fibril meshwork provides articular cartilage with its ability to resist compressive loads applied to the joint during articulation. Maintenance of the components of cartilage extracellular matrix is controlled by the resident chondrocytes that must balance synthetic and degradative processes in order to maintain the integrity of this specialized tissue.
Organisation of Human Aggrecan
The synovial lining of the joint capsule is responsible for maintaining nutrient supply to the articular cartilage and also maintaining low friction during movement through the presence of high concentration of hyaluronan. During the disease process the tissue becomes inflamed and is a contributing factor to the breakdown of articular cartilage.
The research approaches in our laboratories have:
- Focused towards bettering our understanding of the role and mechanisms by which the ADAMTS proteinases are invovled in the destruction of aggrecan in cartilage.
- Investigating potential biomarkers that can be used for diagnosis, distinguishing disease progression and monitoring the efficacy of surgical and therapeutic interventions.
We use a multi disciplinary approach in our work that encompasses the use of monoclonal antibody technologies, protein isolation, purification and characterisation and molecular biology techniques. We are using an established panel of neoepitope antibodies to study the catabolic products generated by ADAMTS proteinases in articular cartilage in both in vitro culture systems (which mimic degradative processes during disease) as well as synovial fluids from patients diagnosed with different joint pathologies. This work will ultimately lead to the discovery of specific markers for joint diseases and therefore aid in the development of pharmaceutical inhibitors of key enzymes such as aggrecanase(s) which will then be developed for use in humans, thereby preventing or limiting the progression of cartilage erosion in osteoarthritis.
In addition, we are using monoclonal antibodies recognising the aggrecanases to elucidate the mechanism by which these enzymes are produced and processed during normal tissue homeostasis and in disease. Molecular Biology approaches have led to the discovery of an alternative-splice variant of ADAMTS-4 found only in cells derived from the synovial lining of patients diagnosed with osteoarthritis. Furthermore, the large panel of monoclonal antibodies we have produced are now being used to develop ELISA-based assay kits for identification of biomarkers expressed in the pathogenesis of musculoskeletal diseases.
Current Sources of Funding
- Arthritis Research UK
Professor Sally Roberts
Professor James Richardson
Professor Hideaki Nagase
Dr Laurence Glennon-Alty