Prostaglandin G/H Synthase-2 (PGHS-2) Is A Key Regulator Of Skeletal Adaptation And Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$301,018.00
Summary
Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing inflammation, has considerable clinical significance. Specific inh ....Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing inflammation, has considerable clinical significance. Specific inhibition of PGHS-2 by recent anti-inflammatory drugs avoids formation of gastric ulcers, but their influence on normal bone remodelling and fracture repair is not known and must be investigated. Many such inhibitors are in advanced clinical trials, but their effect on bone metabolism has not been published. This project is important because it employs novel experimental models to advance our knowledge of prostaglandin biology in skeletal adaptation, and elucidates important clinical consequences for specific inhibition of PGHS-2 in the skeleton. This project will investigate the regulation of prostaglandin production by PGHS enzymes following mechanical loading in vivo. It will use cell, molecular and histochemical techniques to determine if the genes that regulate the enzymes are influenced by mechanical stimuli, and if they are dependent on other molecules, associated with structural proteins (stress fibres) within the cell. It will investigate if inhibition of PGHS-2 by antiinflammatory drugs or stress-fibre inhibitors, depresses normal bone turnover and healing responses. The outcome of these experiments could indicate new approaches to stimulate bone formation, preserve bone mass, or minimise adverse skeletal effects of anti-inflammatory treatments related to orthopaedic or dental procedures.Read moreRead less
Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic Overexpression.
Funder
National Health and Medical Research Council
Funding Amount
$440,750.00
Summary
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover whe ....This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe this will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This will be tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic mice at different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone turnover, such as postmenopausal bone loss. This will be tested by examining the bone structure and gene expression in adult mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to mechanical loading, we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing activity. We will investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled manner and then analysing the bone structure. Knowledge of specific pathways by which bone formation can be stimulated is important for developing novel approaches to induction and augmentation of osteogenesis in skeletal diseases associated with ageing or disability, or for maintenance of new bone around implants. The discovery that COX-2 is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a pharmacological target for modulating inflammation, has considerable clinical significance. Exploiting this knowledge requires precise knowledge of the role of this enzyme in bone remodelling and adaptation and our experiments will contribute significantly to that knowledgeRead moreRead less
Regulation Of Prostaglandin Endoperoxide Synthase-2 In The Human Fetal Membranes At Birth
Funder
National Health and Medical Research Council
Funding Amount
$249,750.00
Summary
Preterm birth with the resulting immaturity of babies is the leading cause of death and disease among newborns. Early birth occurs in 6 to 11% of pregnancies, and its rate is slowly increasing in industrialized countries. We need a much better knowledge of the regulation of the parturition process to find ways to reverse this trend. Prostaglandins are hormonal substances that stimulate uterine contractions, cervical dilatation and membrane rupture. Intrauterine tissues produce prostaglandins, an ....Preterm birth with the resulting immaturity of babies is the leading cause of death and disease among newborns. Early birth occurs in 6 to 11% of pregnancies, and its rate is slowly increasing in industrialized countries. We need a much better knowledge of the regulation of the parturition process to find ways to reverse this trend. Prostaglandins are hormonal substances that stimulate uterine contractions, cervical dilatation and membrane rupture. Intrauterine tissues produce prostaglandins, and an increase of prostaglandin levels in the uterus is likely responsible for inducing labour both normally and preterm. We have previously identified an enzyme protein in the fetal membranes, called prostaglandin synthase-2, that has a key role in the synthesis of intrauterine prostaglandins during pregnancy. This enzyme is increasingly expressed before labour onset. In the present application, we propose studies to determine what causes the increased expression. We hypothesize that the gene encoding this enzyme is specifically activated in the fetal membranes in preparation for labour. We will define the mechanism of regulation by determining the activity of the gene in tissues from women who deliver either spontaneously or without labour at term and preterm. Further, we will determine the interaction of regulatory proteins with the prostaglandin synthase-2 gene in these pregnancies in order to understand the mechanisms of regulation at the molecular level. Finally, we will conduct cell culture studies to experimentally manipulate prostaglandin synthase-2 gene activity in fetal membrane cells. As an overall outcome of this work, new targets may be identified for drugs to disrupt prostaglandin synthase-2 gene activation specifically in the fetal membranes. The long term perspective is to block prostaglandin synthesis in the uterus in order to suppress preterm labour and prevent preterm birth.Read moreRead less
Contribution Of Disturbed Blood Flow And Cerebral Metabolism To White Matter Damage In The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$369,375.00
Summary
It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral ....It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral palsy. Such outcomes are often associated with the presence of asphyxia and infection during pregnancy, leading to the belief that the damage first arises while the baby is still in utero. In this application we suggest that asphyxia and-or infection during pregnancy cause prolonged disturbances in the regulation of blood flow and integrity of the blood-brain barrier in the developing brain, together with changes in metabolism that result in accumulation of prostaglandins and the toxic hydroxyl radical, leading irreversibly to cell death. If this series of events proves to be true, we have suggested and will test several protocols for protecting the fetal brain, which should be readily translatable to clinical practice.Read moreRead less
COX-2 Inhibitors And The Development Of Unstable Angina And Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$171,450.00
Summary
Anti-inflammatory drugs (sometimes called NSAIDs) are widely used in the treatment of arthritis and also as general purpose pain killers. Up to 10 million prescriptions are written each year for these drugs in Australia. Some of the older versions of these drugs like ibuprofen (eg Brufen) and naproxen (trade name Naproxen) cause side effects which can be serious. Damage to the stomach is a particular problem and this can lead to serious bleeding or perforation of ulcers. Less well recognized are ....Anti-inflammatory drugs (sometimes called NSAIDs) are widely used in the treatment of arthritis and also as general purpose pain killers. Up to 10 million prescriptions are written each year for these drugs in Australia. Some of the older versions of these drugs like ibuprofen (eg Brufen) and naproxen (trade name Naproxen) cause side effects which can be serious. Damage to the stomach is a particular problem and this can lead to serious bleeding or perforation of ulcers. Less well recognized are the adverse effects of these drugs on the heart and the kidneys. The older fashioned members of this class of drug are rapidly being replaced by newer agents known as COX-2 inhibitors. Popular examples in Australia are celecoxib (trade name Celebrex) and rofecoxib (trade name Vioxx). These drugs are heavily promoted as being safer than the older NSAIDs. In the case of the stomach, this claim seems to be correct. However, the effects of the new COX-2 inhibitors on the circulation have not been fully assessed. Recently, claims have been made that these drugs may increase the risk of heart attacks. If this were true, it would be an effect that was unique to COX-2 inhibitors as it has not been reported with the older NSAIDs. We plan to carry out a 3 year study in Newcastle hospitals in which we compare the use of COX-2 inhibitors in a group of patients admitted to hospital with a heart attack or unstable angina with that of a control group of patients who were admitted to hospital around the same time, but not for heart problems. We are interested in whether COX-2 inhibitors are associated with an increased risk of heart attacks and whether use of small doses of aspirin protects against this effect. Depending on the results we may be able to improve the safety of these drugs in patients at risk of heart attacks.Read moreRead less