The Role Of A Novel Extracellular Matrix Protein, WARP, In Cartilage Development, Function And Pathology
Funder
National Health and Medical Research Council
Funding Amount
$482,500.00
Summary
The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is ....The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is an important constituent of the three-dimensional structure of the extracellular matrix of the articular surface of cartilage. We can show that WARP forms large-scale structures in tissue culture experiments and in extracts from mouse cartilage, and we have some new data which suggests that WARP interacts specifically with collagen II, a large and quantitatively major component of cartilage. We will explore the function of WARP in cartilage and include in vitro experiments that will reveal information about its distribution, tissue forms, and interactions with other extracellular matrix components (PART 1). To define the in vivo role of WARP we will generate a WARP gene knockout mouse (PART 2). These experiments will provide valuable information about the structure of the cartilage in the joint on the surface of bone and in particular the function of WARP in this structure. Since WARP is at the articular cartilage surface we asked whether WARP is lost in cartilage degeneration. In cartilage tissue grown in vitro under conditions that promote cartilage degradation, WARP is fragmented and released from the cartilage surface. We will explore this further in in vitro and in vivo models of cartilage breakdown (PART 3). Thus, in addition to promoting a new understanding of cartilage structure WARP has the exciting potential to become a specific biomarker for arthritis a major joint degenerative disease with high medical and financial cost to the community.Read moreRead less
QUANTITATIVE ASSESSMENT OF LOOSENING IN HIP ARTHROPLASTIES USING MECHANICAL VIBRATION DIAGNOSTICS
Funder
National Health and Medical Research Council
Funding Amount
$185,665.00
Summary
Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength, fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because of loosening at some stage of their working life. Th ....Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength, fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because of loosening at some stage of their working life. This is becoming a major concern to health services around the world since revision surgery is associated with a higher risk to the patient and costs are far greater than for the primary operation. Current diagnostic techniques using radiographic imaging are both invasive and lack diagnostic accuracy. The ability to detect joint loosening and to discriminate between the various causes of joint loosening following arthroplasty is of great importance to the success of subsequent care plans. This study will be the first in the world to assess the validity of a new diagnostic test that uses low energy mechanical vibration to quantify the degree of loosening in both components of the implanted hip joint. Once the technique has been proven it could readily be extended to evaluate the degree of fixation of other implanted prostheses used to replace the knee, ankle or joints of the upper limbs.Read moreRead less
Understanding How Endogenous G-CSF Mediates Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$531,485.00
Summary
Rheumatoid Arthritis (RA) is a common chronic inflammatory disease which targets joints. Currently, there is no cure for RA and the available anti-rheumatic drugs have limited efficacy and frequent side effects. Progress has been made in understanding the molecular pathways which drive RA and the disease is characterised by high levels of inflammatory mediators (called cytokines). This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice. The ....Rheumatoid Arthritis (RA) is a common chronic inflammatory disease which targets joints. Currently, there is no cure for RA and the available anti-rheumatic drugs have limited efficacy and frequent side effects. Progress has been made in understanding the molecular pathways which drive RA and the disease is characterised by high levels of inflammatory mediators (called cytokines). This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice. These inhibitors work well for some, but not all, patients. The reason why certain RA patients fail to respond to this treatment is not clear. There is great interest in identifying new cytokines in RA and in developing more effective cytokine inhibitors. Our recent research shows that a cytokine best known for its effect on blood cell development (granulocyte-colony stimulating factor or G-CSF) also plays a major role in experimental models of RA. This discovery has led to two Australian biotechnology companies - Zenyth Therapeutics Ltd., and Murigen Therapeutics Ltd, entering into a partnership to develop G-CSF antagonists for clinical trials. However, before we can take such antagonists to the clinic, we need to conduct careful pre-clinical studies to understand the basis for our findings on G-CSF in much greater detail. This will ensure this new therapy is used in the safest and most effective way.Read moreRead less
Molecular Mechanisms Of Cartilage Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$457,517.00
Summary
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the mo ....Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the molecular changes and pathways involved in both the onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with tissue availability from this small animal species. Successful completion of these studies will for the first time allow identification of the complex changes that occur in early OA. An important and likely outcome of this research will be identification of novel matrix proteins and regulatory molecules that will provide critical information for the development of new diagnostic and therapeutic approaches to OA.Read moreRead less
Laser Acupuncture In Patients With Chronic Knee Pain: A Randomised Placebo-controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$701,120.00
Summary
Chronic knee pain is a common and disabling musculoskeletal condition that causes a loss of functional independence and results in significant health care costs. In the majority of patients the most common cause is osteoarthritis. Acupuncture is a form of non-surgical treatment commonly sought by patients and often recommended by GP's. The main outcomes from our project are to establish the role, clinical effectiveness and cost benefit of laser and needle acupuncture in knee pain patients.
Disruption And Restoration Of Motor Control In Musculoskeletal Pathology: Implications For Physiotherapy Management
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
The way in which the nervous system controls muscles and movement may play a role in the development and progression of common musculoskeletal conditions. One of these conditions is patellofemoral pain syndrome which is associated with pain around the knee cap. This condition may result from an imbalance in the activity of the thigh muscles that control movement of the knee cap as the knee bends and straightens. This imbalance is due in part to problems with the control of the muscles by the ner ....The way in which the nervous system controls muscles and movement may play a role in the development and progression of common musculoskeletal conditions. One of these conditions is patellofemoral pain syndrome which is associated with pain around the knee cap. This condition may result from an imbalance in the activity of the thigh muscles that control movement of the knee cap as the knee bends and straightens. This imbalance is due in part to problems with the control of the muscles by the nervous system. Our previous studies have shown that physiotherapy treatment aimed at restoration of the control of the knee muscles results in clinical improvement of the condition. The first part of this project will investigate possible reasons for this muscle imbalance including the effects of pain, swelling and muscle fatigue. Understanding the reasons for the imbalance in muscle activity will help direct and refine more appropriate treatment strategies for this and other musculoskeletal conditions. The second part will assess whether a specific physiotherapy muscle training program for the thigh muscles is more effective in correcting the muscle imbalance than a more generalised thigh strengthening exercise program. The results will help us to better understand why the condition occurs and how we can best assess and treat the problem.Read moreRead less