How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
Development And Pre-clinical Evaluation Of G-DSF Inhibitors For Inflammatory Joint Disease
Funder
National Health and Medical Research Council
Funding Amount
$88,329.00
Summary
G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in expe ....G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in experimental models of inflammatory joint disease. We propose to develop inhibitors of G-CSF as a novel form of anti-cytokine therapy for inflammatory joint disorders, such as rheumatoid arthritis.Read moreRead less
Synovial Macrophages And T-cells Are Therapeutic Targets In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$658,761.00
Summary
Osteoarthritis (OA) is the most widespread musculoskeletal disease in Australia and there are currently no therapies that halt disease progression. Specific inflammatory events play a pivotal role in initiating and driving OA progression. In this study we will define the specific inflammatory cells involved in OA, how and why they change with time, and which can be targeted to stop disease onset and development. This will provide the platform for initiating human clinical trials.
Towards A Rational Strategy For Osteoarthritis Therapy
Funder
National Health and Medical Research Council
Funding Amount
$945,993.00
Summary
Osteoarthritis is the most common form of arthritis, causing disability and chronic pain, for which there are no adequate treatments. Our laboratory has shown that a particular protein is involved in inflammatory arthritis and pain. Blocking this protein in patients with rheumatoid arthritis is showing success. In this project we will carry out some preclinical studies to determine whether blockade of this protein may also be a therapeutic target for osteoarthritis pain and disease.