inflammation-mediated bone loss
by modulation of estrogen signalling
Fractures are associated with suffering, increased mortality and great costs for society. Inflammation is associated with pathological bone loss and thereby an increased risk of fracture. Estrogen protects against bone loss and prevents fractures. However, the use of this hormone as a therapeutic drug against bone loss is restricted due to severe side-effects. The main aim of this project is to characterize the mechanisms behind the protective effects of estrogen on inflammation-mediated bone loss in order to facilitate the development of new bone-specific treatment strategies which avoid the adverse effects.
To this aim we will develop and use novel transgenic mouse models to determine the importance of specific domains and posttranslational modification sites of the estrogen receptor alpha (ERa), the main mediator of estrogenic bone-protective effects (project 1), and identify the target cell types mediating the bone-protective effects (project 2). Furthermore, my recent pivotal finding that expression of ERa in neural cells affects bone mass, published in Proc Natl Acad Sci USA, 2012, will be further explored by gene silencing of ERa using viral vectors to determine the importance of central effects of estrogen for inflammation-mediated bone loss (project 3).
These experimental studies will facilitate the development of new therapeutic strategies to prevent inflammation-mediated bone loss and associated fractures but lack adverse effects.