THE ROLES OF IGF-1 AND GLUCOCORTICOIDS IN BONE REMODELING

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

Description (Taken from the application): Insulin-like growth factor I (IGF-I) and glucocorticoids have particular relevance to skeletal physiology and pathophysiology and a study of their effects on bone is well integrated with the central theme of the, program project. Cells of the osteoblast lineage produce IGF-I, which acts as a local anabolic factor in bone remodeling. There is an association between serum IGF-I levels and bone mass in humans and mice, and it has been suggested that the pathogenesis of glucocorticoid-induced osteoporosis involves a decrease in bone formation due in part to the down-regulation of IGF-I expression. During the present grant cycle, we characterized loss- and gain-of-function mouse models to address the biology and therapeutic potential of IGF-I in bone, as well as to determine the role of IGF-I in glucocorticoid responses. We developed a bone-targeted IGF-I transgenic overexpression mouse that may have increased bone turnover. We showed that glucocorticoids down-regulate collagen synthesis in part by an IGF-I independent pathway in fetal bone organ cultures. Recently, we generated a novel transgenic mouse model with disrupted glucocorticoid signaling in osteoblasts to further explore glucocorticoid pathways in bone. This proposal builds on our research efforts in these areas using mouse models and an in vivo experimental approach. The hypotheses to be tested are that genetic alteration of IGF-I expression in bone will result in corresponding changes in bone mass, and that disruption of glucocorticoid signaling in osteoblasts will block the function of endogenous glucocorticoids in bone and prevent the catabolic effects of pharmacological doses of glucocorticoids. Our specific aims are: (1) to examine the bone phenotype of IGF-I loss-of-function models and the response of these bones to glucocorticoids; (2) to examine bone remodeling in IGF-I gain-of-function models; and (3) to characterize the bone phenotype of transgenic mice with disrupted glucocorticoid signaling. These studies will give new insights into the roles of IGF-I and glucocorticoids in bone remodeling.