This proposal is based on the hypothesis that ICER, the inducible cAMP early repressor, represents a novel mechanism for regulating parathyroid hormone (PTH)-induced gene transcription in osteoblastic cells. PTH, the major calcium-regulating hormone in humans, stimulates bone resorption and can increase or decrease bone formation depending on its mode of administration. PTH elicits these responses by regulating gene expression in osteoblastic cells. Inducible cAMP early repressor (ICER) is a member of the ATF/CREB transcription factor family. ICER is transcribed from an intronic promoter of the cAMP response element modulator (CREM) gene and acts as a dominant negative repressor of cAMP-dependent gene transcription. We recently discovered that PTH and cAMP induced ICER in osteoblastic cell lines and mouse calvariae. WE also found that overexpression of ICER repressed PTH-dependent transcription of a primary response gene in osteoblastic cells. However, the lowest concentration of overexpressed ICER also enhanced transcription, suggesting that ICER is not strictly a repressor. Based on our preliminary data, we hypothesize that the expression of ICER in osteoblasts may not only mediate the attenuation PTH-dependent gene expression but may also augment the induction phase of transcription. We predict that perturbation of ICER levels in osteoblastic cells will alter the pattern of PTH-dependent gene expression and result in deregulation of PTH bioactivities. To address these hypotheses, we propose the following specific aims: (1) To determine the role of ICER in modulating the expression of selected PTH-inducible primary response genes in cultured osteoblastic MC3T3-E1 cells using overexpression and antisense strategies; (2) To determine the temporal and spatial pattern of ICER expression in vivo in response to injections and infusion of PTH; and (3) To determine the function of ICER in vivo by generating transgenic mice that have bone-directed ICER overexpression and by examining CREM knockout mice that lack ICER expression. The experiments proposed here are a first step in understanding the role of ICER in modulating PTH-dependent gene expression and function in bone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046542-03
Application #
6497417
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
2000-02-08
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$232,384
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Chandhoke, Taranpreet K; Huang, Yu-Feng; Liu, Fei et al. (2008) Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor. Bone 43:101-9
Liu, Fei; Lee, Sun-Kyeong; Adams, Douglas J et al. (2007) CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment. Bone 40:1135-43
Liu, F; Huang, Y-F; Kream, B E (2005) Identification of novel cAMP responsive element modulator (CREM) isoforms expressed by osteoblasts. Calcif Tissue Int 77:91-5
Nervina, J M; Tetradis, S; Huang, Y-F et al. (2003) Expression of inducible cAMP early repressor is coupled to the cAMP-protein kinase A signaling pathway in osteoblasts. Bone 32:483-90