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.
Microbiology and Molecular Genetics
School of Medicine
Linkhart, Thomas A.
Casiano, Carlos A.
Strong, Donna D.
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
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
Loma Linda University Libraries
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.
Perez-Casellas, Laura A., "Regulation of IGFBP-5 and Osteoblast Functions by Nuclear Factor I" (2013). Loma Linda University Electronic Theses, Dissertations & Projects. Paper 145.
Loma Linda University Electronic Theses & Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives