SEX STEROID REGULATION OF IGF-I EXPRESSION IN BONE

Summary

Principal Investigator: Thomas McCarthy
Abstract: DESCRIPTION: (Adapted from the applicant's abstract) Bone mass is balanced by opposing processes of resorption and formation. Insulin-like growth factor-I (IGF-I) is an important bone growth factor that enhances replication of less differentiated bone cells and matrix collagen synthesis by osteoblasts. Parathyroid hormone and prostaglandin E2 increase cAMP levels in osteoblasts, and intermittent administration of either agent stimulates bone formation. These hormones act in part through a process that relies on cAMP dependent protein kinase A, inducing osteoblasts to express IGF-I. The investigator has identified a C/EBP site that is necessary and sufficient for cAMP-dependent IGF-I promoter activation, found C/EBP delta to be the functional trans-acting transcription factor in fetal rat osteoblasts, and also found that estrogen directly suppresses the stimulatory effect of cAMP on C/EBP delta-mediated IGF-I activation, but not on cAMP synthesis. This is estrogen receptor dependent and does not require an identifiable estrogen response elements or AP-1 binding sequence. The proposed studies will examine protein:protein interactions that influence C/EBP mediated IGF-I activation, and the counter-regulatory suppressive effect of estrogen on IGF-I gene activation. The investigator will determine the molecular actions of PGE2 and l7beta-estradiol on C/EBP delta and C/EBP beta expression by characterizing functional cis- and trans-acting elements that regulate their promoter function, and determine the ability of these agents to modulate C/EBP mRNA stability. He will determine the influence of PKA activation in the absence or presence of l7beta-estradiol co-treatment on translocation of C/EBP delta and beta from the cytoplasm to the nucleus and analyze changes in C/EBP phosphorylation under these conditions. Finally, he will determine the physiologic role of C/EBP delta and beta in cAMP activated IGF-I expression, interactions with estrogen, and ultimately in regulating bone mass in C/EBP knockout animals. Bone mass studies will be conducted using peripheral quantitative computer tomography, and will be correlated with basal and activated skeletal IGF-I expression.
Funding Period: 2000-05-01 - 2004-04-30
more information: NIH RePORT

Top Publications

  1. pmc Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase
    Puneet Dhawan
    Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
    Mol Cell Biol 25:472-87. 2005
  2. ncbi Interactions between CCAAT enhancer binding protein delta and estrogen receptor alpha control insulin-like growth factor I (igf1) and estrogen receptor-dependent gene expression in osteoblasts
    Weizhong Chang
    Department of Surgery, Yale University School of Medicine, New Haven, CT 06520 8041, USA
    Gene 345:225-35. 2005

Detail Information

Publications2

  1. pmc Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase
    Puneet Dhawan
    Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
    Mol Cell Biol 25:472-87. 2005
    ..These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D(3) that involves the regulation of VDR transcription...
  2. ncbi Interactions between CCAAT enhancer binding protein delta and estrogen receptor alpha control insulin-like growth factor I (igf1) and estrogen receptor-dependent gene expression in osteoblasts
    Weizhong Chang
    Department of Surgery, Yale University School of Medicine, New Haven, CT 06520 8041, USA
    Gene 345:225-35. 2005
    ..Their combined effects on one important gene target, igf1, may help to determine the balance in the overall rates of bone formation...