Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor

Nick Z. Lu, Jennifer B. Collins, Sherry F. Grissom, John A. Cidlowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7143-7160
Number of pages18
JournalMolecular and cellular biology
Issue number20
StatePublished - Oct 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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