The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts

Bibliographic Details
Main Author:	Sutton, Amelia L.
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2005
Subjects:	vitamin D VDR osteoblasts osteoclasts bone skeleton bone mass transcription
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1121820822

id	ndltd-OhioLink-oai-etd.ohiolink.edu-case1121820822
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case11218208222021-08-03T05:31:59Z The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts Sutton, Amelia L. vitamin D VDR osteoblasts osteoclasts bone skeleton bone mass transcription Vitamin D is essential for calcium and phosphate homeostasis and for protecting skeletal mineralization. The primary targets of 1,25(OH)2D3, the most bioactive derivative of vitamin, are the intestine and the kidney where this hormone stimulates mineral absorption or reabsorption to maintain appropriate serum concentrations of calcium and phosphate. By tightly regulating systemic mineral ion levels, 1,25(OH)2D3 prevents mobilization of calcium and phosphate stores from the bone, and, thus indirectly protects bone mineral density. However, 1,25(OH)2D3 also directly influences bone tissue by modulating the activities of osteoblasts, bone-forming cells, and osteoclasts, bone-resorbing cells. 1,25(OH)2D3 can either inhibit or promote bone mineralization depending on the physiological or pathophysiological state of the organism. The goal of this dissertation was to more fully understand the pleiotropic effects of 1,25(OH)2D3 in the bone by analyzing individual 1,25(OH)2D3-induced target genes. To this end, we have identified a multitude of 1,25(OH)2D3-regulated genes in osteoblastic cells through global gene expression profiling. We have chosen four induced genes, MN1, C/EBPâ, SEMA3B, and thrombomodulin, to further characterize by exploring the regulation and function of these targets in both isolated osteoblastic cells and in the more complex bone environment. First, this dissertation uncovers both a molecular and a cellular function for MN1, a transcription factor first identified as a gene disrupted in meningiomas, in augmenting 1,25(OH)2D3-stimulated transcription and in restricting cell growth. Second, our findings suggest that a cooperative interplay exists between VDR and the transcription factor C/EBPâ in regulating gene expression and in modulating bone density. Third, analysis of mice overexpressing SEMA3B, a secreted cell adhesion molecule, indicates that high levels of this protein causes severe osteopenia due to enhanced osteoclastogenesis and bone resorption. Finally, overexpression of thrombomodulin, a transmembrane anticoagulant protein, accelerates osteoblast proliferation. Osteoblast-selective disruption of thrombomodulin does not result in overt skeletal abnormalities, but further analyses are required to fully understand the function of thrombomodulin in bone. Future studies exploiting the in vitro and in vivo tools developed in this work will provide a more complete picture of the multiple functions of 1,25(OH)2D3 and its target genes in the bone. 2005-07-26 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1121820822 http://rave.ohiolink.edu/etdc/view?acc_num=case1121820822 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	vitamin D VDR osteoblasts osteoclasts bone skeleton bone mass transcription
spellingShingle	vitamin D VDR osteoblasts osteoclasts bone skeleton bone mass transcription Sutton, Amelia L. The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
author	Sutton, Amelia L.
author_facet	Sutton, Amelia L.
author_sort	Sutton, Amelia L.
title	The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
title_short	The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
title_full	The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
title_fullStr	The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
title_full_unstemmed	The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
title_sort	regulation and function of 1,25-dihydroxyvitamin d3-induced genes in osteoblasts
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2005
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1121820822
work_keys_str_mv	AT suttonamelial theregulationandfunctionof125dihydroxyvitamind3inducedgenesinosteoblasts AT suttonamelial regulationandfunctionof125dihydroxyvitamind3inducedgenesinosteoblasts
_version_	1719421385028141056

The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts

Similar Items