Abstract

The Insulin-like Growth Factor (IGF) system is a major target of GC inhibition in bone. We found that GCs inhibit expression of IGF binding protein-5 (IGFBP5) which binds IGFs and stimulates osteoblast activity by IGF dependent and independent mechanisms. GC-induced inhibition of IGFPB5 promoter activity was mediated by a composite response element that has binding sites for transcription factor activator protein 2 (AP-2) and nuclear factor I (NFI). The work in this dissertation identifies the NFI gene family as an important regulator of IGFBP-5 transcription primarily in human, as well as murine osteoblasts. The mechanism of IGFBP5 gene regulation involves direct binding of the NFI members to its cis element located in the IGFBP5 promoter region. Knockdown of NFI mRNA expression had diverse effects on IGFBP5 expression depending on the gene isoform member, suggesting that NFI isoforms have different roles regulating this gene. NFI had important roles during the process of osteoblast differentiation and mineralization, in the MCT3T3-E1 cell culture model. Knockdown of murine Nfix gene expression delayed the mineralization of this cell line, and also decreased mRNA expression levels of early and late osteoblastogenesis makers, in particular osteocalcin. An understanding of the role of the NFI gene family and the role of this family in the process of osteoblastogenic maker gene regulation can provide a new alternative for pharmacological target genes for the treatment of osteoporosis, a condition that widely affects Americans.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology

School

School of Medicine

First Advisor

Linkhart, Thomas A.

Second Advisor

Casiano, Carlos A.

Third Advisor

Duerksen-Hughes, Penelope

Fourth Advisor

Farley, John

Fifth Advisor

Strong, Donna D.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2013

Date (Title Page)

3-1-2013

Language

English

Library of Congress/MESH Subject Headings

Osteoblasts; Insulin-Like Growth Factor-Binding Protein 5; Genes, Regulator; Osteoporosis

Subject - Local

Insulin-like Growth factor, IGF binding protein-5, Nuclear Factor I, Osteoblastogenic maker gene regulation, osteoporosis

Type

Dissertation

Page Count

114 p.

Digital Format

Application/PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses & Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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