NDORMS DPhil & MSc by Research
Hypoxia, osteoclasts and angiopoietin-like 4: coupling bone and cartilage degradation in arthritis
OUTLINE OF RESEARCH PROPOSAL
Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint conditions characterised by increased erosion and degeneration of articular cartilage and subchondral bone, resulting in joint destruction, pain and loss of function. Osteoclasts are multi-nucleated cells specialised to digest (resorb) bone.
Our recent studies have shown that osteoclasts also contribute to cartilage degradation. Hypoxia and the hypoxia-inducible transcription factor HIF-alpha are driving features of both RA and OA. We have found that hypoxia (2% O2) stimulates osteoclast activity and increases bone resorption, as does the HIF-induced adipokine angiopoietin-like 4 (ANGPTL4). We have also discovered that ANGPTL4 is over-expressed in both damaged OA cartilage and in RA synovial fluid and serum, where it correlates with increased bone destruction.
This project will investigate whether hypoxia and ANGPTL4 also increase the rate of osteoclast-mediated cartilage degradation in these conditions. By investigating the influence of hypoxia and ANGPTL4 on osteoclast-mediated erosion of articular cartilage, we will determine whether osteoclast activity could represent a potential therapeutic target to prevent loss of both bone and cartilage in arthritic disease and other conditions such as primary bone cancer.