Grant: Operating Grant

Glucocorticoids are widely used drugs in the treatment of inflammatory diseases as well as some forms of cancer. Long-term use of these agents is limited by profound skeletal growth inhibition in children and osteoporosis in both children and adults. We are investigating the effects of glucocorticoids on bone to help suggest therapeutic interventions in patients receiving glucocorticoid therapy. Work in my laboratory has shown that glucocorticoids alter the responses of osteoblasts (the cells that make bone) to a number of hormones and neurotransmitters by increasing the amount of G proteins (primarily G11 and to a lesser extent Gs) expressed in the cells. These G proteins transduce the signals from hormone and neurotransmitter receptors to alter cell growth and function. To understand the importance of these changes in G proteins we have created mice in which the G proteins are over-expressed, mimicking the effects of the drugs. In this proposal we are testing the bone density and strength of our transgenic mouse lines that over-express G proteins and observing what happens when we stress their skeletons by feeding them a diet without calcium or removing estrogens in female mice. We will use our transgenic mice to test specific cellular changes and molecular pathways that cause decreased bone density. Finally having identified what the changes in G proteins do to the mouse bones and how they do it we will determine if we can improve their bones with current osteoporosis therapies and try some new drugs that target the specific pathways changed in the bone cells. Together our studies will help us understand how glucocorticoids induce osteoporosis and begin to assess the response of the bones to therapies.