Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic overexpression. [ 2004 - 2006 ]

Research Grant

Researchers: Prof Mark Forwood (Principal investigator) ,  Dr Alan Cassady

Brief description 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 knowledge

Funding Amount $AUD 440,750.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant