A transgenic approach to understanding the role of the endogenous glucocorticoids in bone

Date of Completion

January 2006

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

Although glucocorticoid excess leads to bone loss, the role of the endogenous glucocorticoids in bone is unclear. There is a considerable amount of evidence in vitro showing that glucocorticoids may have anabolic actions. The purpose of this work was to examine the role of endogenous glucocorticoids in vivo. The approach involved a previously cloned, novel transgenic model in which glucocorticoid signaling was diminished in bone. A 2.3-kb fragment of the rat Collal promoter was used to drive the expression of a pre-receptor signaling enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), in mature osteoblasts. In this work, the impact of transgene expression on osteoblast function, bone morphometry, and osteoblast differentiation were examined. Transgenic calvaria had lower collagen production than wild type calvaria. Cortical bone mass was reduced in transgenic femurs. In addition, vertebral trabecular bone volume was reduced and mineralization was impaired in female transgenic mice. Further, both primary calvarial osteoblasts and stromal cultures from male and female transgenic mice showed decreased mineralization compared to wild type cultures. Microarray was also used to identify the expression of genes that were altered in transgenic bone. In summary, disruption of endogenous glucocorticoid signaling in mice led to an impairment of bone acquisition and osteoblast function. ^

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