Glucocorticoid-induced osteoporosis is a major clinical problem for which no therapy is currently available. This is in part due to a lack of knowledge about the direct actions of glucocorticoids in bone. It appears that in vivo one of the major effects of glucocorticoids is the inhibition of bone formation, and in vitro studies have shown that glucocorticoids inhibit bone collagen synthesis. Studies from our laboratory have indicated that insulin-like growth factor (IGF) I and II are among the most prevalent growth factors secreted by bone cells and are potent stimulators of bone collagen synthesis. Recently, we found that cortisol decreases IGF I synthesis and IGF II concentrations in cultures of 21 day fetal rat calvariae and of osteoblast-enriched (Ob) cells from 22 day fetal rat parietal bone. Cortisol also inhibited IGF II binding to Ob cells. In contrast, parathyroid hormone (PTH) and cAMP inducers stimulated skeletal IGF I synthesis. It is our hypothesis that glucocorticoids act by decreasing the synthesis and binding of IGF's in bone cells, and these actions are reversible. Over the course of the next five years we propose to (1) define the exact effects of cortisol on bone formation using histomorphometric analysis, study its mechanisms of action on the inhibition of type 1 bone collagen synthesis at the transcriptional level and define its effects on bone collagen degradation; (2) study the mechanism of action of cortisol in bone and examine the precise level of action on IGF I and II synthesis, and on IGF receptor expression in Ob cells; and (3) determine if PTH and other agents known to stimulate skeletal IGF I synthesis reverse the inhibitory actions of cortisol on IGF I synthesis, and define hormones that reverse the cortisol-induced decrease in skeletal IGF II concentrations and binding to Ob cells. The agents found to modify the inhibitory actions of cortisol on IGF synthesis and binding will be tested to determine if they reverse the inhibitory actions of cortisol on parameters of bone formation in vitro. These studies will provide valuable information on the mechanism of action of cortisol in bone and possibly will form the foundation for logical therapeutic alternatives in glucocorticoid-induced osteopenia.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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St. Francis Hospital and Medical Center
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Yu, Jungeun; Zanotti, Stefano; Walia, Bhavita et al. (2018) The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone. Am J Pathol 188:149-159
Canalis, Ernesto; Yu, Jungeun; Schilling, Lauren et al. (2018) The lateral meningocele syndrome mutation causes marked osteopenia in mice. J Biol Chem 293:14165-14177
Zanotti, S; Yu, J; Bridgewater, D et al. (2018) Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis. Bone 114:198-205
Yu, Jungeun; Zanotti, Stefano; Schilling, Lauren et al. (2018) Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis. Am J Pathol 188:1430-1446
Canalis, Ernesto (2018) MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. Eur J Endocrinol 178:R33-R44
Canalis, Ernesto (2018) Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism 80:48-56
Zanotti, Stefano; Canalis, Ernesto (2017) Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes. Bone 103:159-167
Canalis, Ernesto; Zanotti, Stefano (2017) Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice. J Cell Biochem 118:1819-1826
Zanotti, Stefano; Yu, Jungeun; Sanjay, Archana et al. (2017) Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome. J Biol Chem 292:12232-12244
Canalis, Ernesto; Sanjay, Archana; Yu, Jungeun et al. (2017) An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice. Endocrinology 158:730-742

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