Aera Yoo

Abstract

Micromolar concentrations of aluminum ion (oxidation state of 3 +) consistently stimulated [3H]thymidine incorporation into cell DNA and increased cellular alkaline phosphatase activity (an osteoblastic differentiation marker) in osteoblast-like cells of chicken and human origin. Although biphasic, dose-dependent stimulations were highly reproducible, the maximal stimulatory dose varied among different experiments. Mitogenic doses of aluminum ion also stimulated collagen synthesis in cultured human osteosarcoma TE85 cells. In addition, the same mitogenic concentrations of aluminum ion enhanced the 1,25 dihydroxy vitamin D3-dependent stimulation of osteocalcin secretion. Together, these findings indicate that aluminum at micromolar concentrations, stimulates the proliferation, differentiation, and activity of human osteoblastic-line cells in vitro. With respect to the mechanism of its mitogenic action, the mitogenic concentrations of aluminum ion did not stimulate cAMP production in human osteosarcoma TE85 cells, indicating that the mechanism of aluminum ion does not involve cAMP. Additional studies have also revealed that the mitogenic activity of aluminum ion is different from that of fluoride because (a) unlike fluoride, the mitogenic action of aluminum was unaffected by culture medium changes (/. e., it was not dependent on the presence of essential factors in the cell-conditioned media); (b) unlike fluoride, the mitogenic action of aluminum was not specific for bone cells; and (c) interaction studies with fluoride revealed that aluminum and fluoride did not share the same rate-limiting step(s) for their effects in stimulating the proliferation of osteoblastic-like cells. To test the additional hypothesis that the mitogenic action of aluminum ion is mediated through the insulin-like growth factor (IGF) regulatory system, the effects of mitogenic concentrations of aluminum on IGF-I and IGF-II production were evaluated. TE85 cells treated with aluminum ion for 48 hours showed biphasic stimulation of the synthesis/secretion of IGF-I and IGF-II into the conditioned medium (CM). The addition of IGFBP-4, an inhibitory IGF binding protein, significantly reduced the effect of aluminum to stimulate [3H]thymidine incorporation, supporting the hypothesis that the mitogenic action of aluminum was mediated by an increase in IGF production. Western ligand blot analysis revealed that mitogenic concentrations of aluminum ion also inhibited the secretion of IGF binding proteins, particularly the inhibitory IGFBP-4, an action which could lead to the potentiation of the overall activity of IGFs. Based on these findings, it is concluded that aluminum ion, at micromolar concentrations, acts directly on human bone cells to stimulate their proliferation and differentiation by a mechanism that involves increase in the production and activity of IGFs in bone cells.

LLU Discipline

Biochemistry

Department

Biochemistry

School

Graduate School

First Advisor

K. H. William Lau

Second Advisor

John R. Farley

Third Advisor

E. Clifford Herrmann

Degree Name

Master of Science (MS)

Degree Level

M.S.

Year Degree Awarded

1994

Date (Title Page)

6-1994

Language

English

Library of Congress/MESH Subject Headings

Aluminum -- pharmacology; Insulin-Like Growth Factor I -- metabolism; Insulin-Life Growth Factor II -- metabolism; Osteoblasts -- metabolism; Bone Development -- drug effects; Bone and Bones

Type

Thesis

Page Count

vii; 76

Digital Format

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 and Dissertations

Collection Website

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

Repository

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

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Biochemistry Commons

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