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Molecular and Cellular Biology, October 2007, p. 7143-7160, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00253-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Selective Regulation of Bone Cell Apoptosis by Translational Isoforms of the Glucocorticoid Receptor

Nick Z. Lu ,^1, Jennifer B. Collins,² Sherry F. Grissom,² and John A. Cidlowski^1*

Molecular Endocrinology Group, Laboratory of Signal Transduction,¹ Microarray Center, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709²

Received 12 February 2007/ Returned for modification 16 April 2007/ Accepted 25 July 2007

Glucocorticoids are widely used in the treatment of inflammatory and other diseases. However, high-dose or chronic administration often triggers troublesome side effects such as metabolic syndrome and osteoporosis. We recently described that one glucocorticoid receptor gene produces eight translational glucocorticoid receptor isoforms that have distinct gene-regulatory abilities. We show here that specific, but not all, glucocorticoid receptor isoforms induced apoptosis in human osteosarcoma U-2 OS bone cells. Whole human genome microarray analysis revealed that the majority of the glucocorticoid target genes were selectively regulated by specific glucocorticoid receptor isoforms. Real-time PCR experiments confirmed that proapoptotic enzymes necessary for cell death, granzyme A and caspase-6, were induced by specific glucocorticoid receptor isoforms. Chromatin immunoprecipitation assays further suggested that glucocorticoid receptor isoform-dependent induction of proapoptotic genes was likely due to selective coregulator recruitment and chromatin modification. Interestingly, the capabilities to transrepress proinflammatory genes were similar among glucocorticoid receptor isoforms. Together, these findings provide new evidence that translational glucocorticoid receptor isoforms can elicit distinct glucocorticoid responses and may be useful for the development of safe glucocorticoids with reduced side effects.

Published ahead of print on 6 August 2007.

Present address: Division of Allergy-Immunology, Department of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611.