The effects of osteoblast-targeted BCL-2 overexpression on bone formation

Date of Completion

January 2006

Keywords

Biology, Molecular|Biology, Cell

Degree

Ph.D.

Abstract

Bcl-2 is an important regulator of apoptosis, a process important for the development and homeostasis of self-renewing tissues, including bone. However, little is known about the effect of Bcl-2 in osteoblast activity and bone formation. ^ Using Col2.3Bcl-2 construct, in which 1.8 kb human Bcl-2 cDNA was driven by the 2.3 kb fragment of rat type I collagen promoter, we generated a transgenic mouse with bone-targeted overexpression of Bcl-2. Phenotypically, these mice were smaller than their wild-type littermates and demonstrated an abrogation of sex differences normally observed in +/+ mice. Female +/+ mice demonstrated increased bone turnover with elevated osteoblast and osteoblast parameters compared to +/+ males. The tg/+ mice did not demonstrate such significant differences between sexes, because tg/+ male had a significant increase in ObS/BS, whereas tg/+ females had a significant decrease in BFR and MAR. Tg/+ mice also demonstrated an inhibition of bone loss with age normally occurred in +/+. ^ Ex vivo osteoblast cultures demonstrated that the transgene expression increased dramatically with the differentiation of osteoblasts without any effect on endogenous Bcl-2 and Bax expression. Overexpression of Bcl-2 had no effect on osteoblast proliferation, increased the adhesion and differentiation, but inhibited mineral deposition. Estrogen was shown to stimulate endogenous Bcl-2 message levels in a dose-dependent manner. ^ These studies suggest a role of Bcl-2 in sex and age regulation of bone, and the importance of apoptosis in normal bone formation.^

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