Glucocorticoid Receptor Signaling in the Osteoblast and its Role in Osteoporosis

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DESCRIPTION (provided by applicant): Project Summary: This application proposes mentored career development as a physician-scientist to provide the candidate the foundation necessary for an independent investigative program. The candidate is an academic pediatric endocrinologist whose career goal is to elucidate the mechanisms of glucocorticoid action, with an emphasis on understanding glucocorticoid-induced osteoporosis (GIOP). The proposed period of mentored scientific training in the laboratory of Dr. Louis J. Muglia at Washington University provides an ideal environment to do so, allowing the candidate to develop the scientific skills to become an independent investigator while working alongside an expert in glucocorticoid (GC) physiology and signaling. During this period the candidate will also receive training in the study of bone biology from Dr. Steven Teitelbaum, an expert in bone metabolism. Throughout his career the candidate will maintain a focused and limited pediatric endocrine practice that will guide his research endeavors, though the majority of time will be devoted to clinically relevant research. The central hypotheses that will be tested during the proposed project are as follows: (1) Direct effects of GC on the osteoblast play a major role in GIOP, which will be quantified. (2) These direct GC effects on the osteoblast cause the decrease in bone formation associated with GIOP. (3) GC-induced osteoblast apoptosis, which contributes to the decrease in bone formation, is mediated by the osteoblast glucocorticoid receptor (GR). (4) GCs, through the GR, cause apoptosis in the osteoblast through modulation of specific aspects of PTH signaling. The candidate proposes to test these hypotheses using a recently developed, unique conditional knockout mouse model that inactivates the glucocorticoid receptor in osteoblasts and their precursors. The comparative analysis of these osteoblast GR-deficient mice with GR intact mice will provide answers to the above questions. Information thus gained will further understanding of GIOP, with the intention of one day developing agents that prevent or avoid the bone loss. Relevance to Public Health: Glucocorticoid-induced osteoporosis (GIOP) is now the third leading cause of osteoporosis following post menopausal and senile varieties, and an estimated 30-50% of people experience a fracture during chronic GC treatment. Though it is clear that glucocorticoids cause bone loss and increase the risk of fracture, the mechanism of GIOP is not clear, and therefore it is difficult to develop preventative or improved therapies. Results from the proposed research project may lead to new treatment options for GIOP that preserve the beneficial immunomodulatory effects of glucocorticoids while preventing the bone loss associated with their use.