Modulation Of Osteoclast Formation And Function To Prevent Joint Destruction In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$443,250.00
Summary
Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may ....Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly focused on inflammation, far less is known about the processes responsible for bone damage. Normally, specialised bone cells called osteoclasts carry out bone breakdown during growth and maintenance of the skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore, focuses on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human rheumatoid arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by selectively targeting osteoclasts with an inhibitor known as Osteoprotegerin. Besides Osteoprotegerin, we have identified two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of animals and humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL and sFRP-1 (like Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very important messenger molecule in arthritis called tumour necrosis factor. We therefore propose to study the effect of OCIL and sFRP-1 in the joints of mice with arthritis. We expect that these new inhibitors will have favorable effects on joint damage. If so, they could undergo further testing for use in humans. We believe that investigations along these lines may provide a rationale for an entirely new treatment approach to improve the long term outcome for patients with arthritis.Read moreRead less
Chemokines are small molecules that are released by a number of cell types, particularly monocytes, when inflammation occurs. Chronic inflammatory disease is associated with severe bone erosion and loss of bone quality. Surprisingly, chemokines control osteoclast development as well as macrophage activation; even if the osteoclast has formed, blocking chemokine signalling prevents bone resorption. Chemokines are a new and exciting target to control osteoclast formation.
The Role Of Tenascin-C In Bone And Joint Pathology
Funder
National Health and Medical Research Council
Funding Amount
$215,773.00
Summary
Many diseases of bones (e.g.osteoporosis) and joints (e.g. arthritis) result from the abnormal function of cells in these tissues. Factors regulating cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. Tenascin-C is a protein produced by bone and joint cells. The role of tenascin-C in the function of bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts) will be investigated. We will investigate whether ten ....Many diseases of bones (e.g.osteoporosis) and joints (e.g. arthritis) result from the abnormal function of cells in these tissues. Factors regulating cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. Tenascin-C is a protein produced by bone and joint cells. The role of tenascin-C in the function of bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts) will be investigated. We will investigate whether tenascin-C is required for the bone loss that occurs in female mice when oestrogen is not present. We will also determine the role played by tenascin-C in development and recovery from arthritis. This study will contribute to the understanding of how bone and joint cells function in health and disease.Read moreRead less