Molecular mechanisms of glucocorticoid-induced bone loss

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Glucocorticoid administration is frequently used to suppress inflammation and treat a variety of conditions in the VA patient population. One of the most significant side effects of this therapy is bone loss and increased risk of fracture. We have developed a murine model of glucocorticoid-induced bone loss that mimics many of the structural and histological changes observed in humans. In addition, we have used mice with genetic deletion of the glucocorticoid receptor in specific cell types to identify the targets of glucocorticoid action on the skeleton. We found that deletion of the glucocorticoid receptor from osteoblast lineage cells prevents the stimulation of bone resorption and the suppression of bone formation caused by glucocorticoid administration. However, the molecular mechanisms by which glucocorticoids stimulate bone resorption and suppress bone formation by acting on this cell type remain unclear. Based on preliminary studies, we propose the central hypothesis that glucocorticoids stimulate bone resorption by suppressing expression of osteoprotegerin (OPG) and that they suppress bone formation by antagonizing canonical Wnt signaling. To address this hypothesis we will identify the molecular mechanisms by which glucocorticoids suppress expression of the OPG gene using a combination of large transcriptional reporter constructs and deletion of regulatory sequences from the endogenous OPG gene in cells and mice (Aim 1). We will also determine whether glucocorticoids suppress bone formation by stimulating the apoptosis of osteoblast lineage cells by blocking induction of apoptosis in this cell type. This will be accomplished by deletion of genes essential for apoptosis (Bak, Bax, and Caspase 8) in this cell lineage (Aim 2). Lastly, we will determine whether glucocorticoids suppress bone formation by opposing Wnt signaling by creating mice with constitutive activation of β-catenin in osteoblasts and treating them with exogenous glucocorticoids. If our hypothesis is correct, this maneuver will prevent suppression of bone formation by glucocorticoids (Aim 3). Overall, the proposed studies will clarify the molecular changes by which glucocorticoid excess causes bone loss and may identify novel approaches to prevent this bone loss in patients that require chronic glucocorticoid therapy.