Osteoporosis is often a consequence of glucocorticoid therapy and pathological conditions in which endogenous glucocorticoid level are elevated. Glucocorticoid induced osteoporosis is due to an increase of bone resorption and a decrease in bone formation. Glucocorticoids are important regulators of bone formation, although, their effects are often paradoxical. While physiologic concentrations of glucocorticoids promote osteoblast differentiation in primary cultures of calvarial and bone marrow stromal cells, pharmacological concentrations inhibit bone formation by decreasing osteoblast renewal and function. Insulin-like growth factor I (IGF-I), however, is anabolic for bone formation. It been have previously shown that IGF-I can prevent the inhibitory effects of glucocorticoids in organ cultures of fetal rat calvaria. In this proposal, we will take advantage of transgenic approaches to design new and more definitive strategies for assessing the effects and interactions of Gcs and IGF-I on bone formation. First, it is hypothesize that overexpression of IGF-I in bone will increase bone formation and prevent the inhibitory effects of glucocorticoids in vivo. Second, it is suggested that IGF-I null mice will have defects in bone formation and will be susceptible to the inhibitory effects glucocorticoids on bone formation. Third, it is hypothesized that in vivo glucocorticoids willlimit the osteogenic differentiation of ex vivo bone marrow stromal cell cultures by depleting the marrow of progenitors. These hypotheses will be addressed will be addressed with the following models: A unique trans-genic mouse will be developed in which IGF-I expression is specifically targeted to bone by a COL1A1 promoter fragment that is highly expressed in bone but not most other tissues. Organ cultures of calvaria from fetal IGF-I null mice will be studied. Finally, mice with be treated with glucocorticoids in vivo and the differentiation of ex vivo bone marrow stromal cell cultures examined in vitro. These studies will provide insights in to the interactions of glucocorticoids and IGF-I on bone and show whether or not targeted growth factor expression in mice will prevent the inhibitory effects of glucocorticoids on bone formation.

Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Marijanovic, Inga; Kronenberg, Mark S; Erceg Ivkosic, Ivana et al. (2009) Comparison of proliferation and differentiation of calvarial osteoblast cultures derived from Msx2 deficient and wild type mice. Coll Antropol 33:919-24
Zhang, W; Pantschenko, A G; McCarthy, M-B et al. (2007) Bone-targeted overexpression of Bcl-2 increases osteoblast adhesion and differentiation and inhibits mineralization in vitro. Calcif Tissue Int 80:111-22
He, Jianing; Rosen, Clifford J; Adams, Douglas J et al. (2006) Postnatal growth and bone mass in mice with IGF-I haploinsufficiency. Bone 38:826-35
Lengner, Christopher J; Steinman, Heather A; Gagnon, James et al. (2006) Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol 172:909-21
Delahunty, K M; Shultz, K L; Gronowicz, G A et al. (2006) Congenic mice provide in vivo evidence for a genetic locus that modulates serum insulin-like growth factor-I and bone acquisition. Endocrinology 147:3915-23
Sher, L B; Harrison, J R; Adams, D J et al. (2006) Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-targeted disruption of glucocorticoid signaling. Calcif Tissue Int 79:118-25
Jiang, Jin; Lichtler, Alexander C; Gronowicz, Gloria A et al. (2006) Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 39:494-504
Lee, Sun-Kyeong; Gardner, Amy E; Kalinowski, Judith F et al. (2006) RANKL-stimulated osteoclast-like cell formation in vitro is partially dependent on endogenous interleukin-1 production. Bone 38:678-85
Pantschenko, Alexander G; Zhang, Wenjian; Nahounou, Marcia et al. (2005) Effect of osteoblast-targeted expression of bcl-2 in bone: differential response in male and female mice. J Bone Miner Res 20:1414-29
Kim, Nacksung; Kadono, Yuho; Takami, Masamichi et al. (2005) Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med 202:589-95

Showing the most recent 10 out of 94 publications