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Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20-binding enhancer

Nathalie Leclerc1, Tommy Noh, Arvinder Khokhar

  • 1University of Southern California Keck School of Medicine, Los Angeles 90033, USA.

Arthritis and Rheumatism
|March 8, 2005
PubMed
Abstract

Insights

Glucocorticoids inhibit osteocalcin (OC) gene expression in bone cells by repressing an Egr2/Krox20 enhancer. This mechanism likely contributes to glucocorticoid-induced osteoporosis, a common side effect of these drugs.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Bone Biology

Background:

  • Glucocorticoids are essential for managing rheumatoid arthritis but induce osteoporosis by inhibiting bone formation.
  • Osteocalcin (OC) gene expression is crucial for bone development and is suppressed by glucocorticoids.
  • Understanding the transcriptional mechanisms underlying this suppression is key to mitigating side effects.

Purpose of the Study:

  • To identify glucocorticoid-sensitive transcriptional mechanisms regulating osteocalcin (OC) gene expression in osteoblasts.
  • To elucidate the role of specific transcription factors and their binding sites in glucocorticoid-mediated repression of OC.

Main Methods:

  • Utilized murine MC3T3-E1 osteoblastic cultures treated with dexamethasone (DEX).
  • Employed stable and long-term transient transfection assays with OC promoter-reporter constructs to map glucocorticoid response elements (GREs).
  • Investigated transcription factor binding using electrophoretic mobility shift assays (EMSAs).

Main Results:

  • A novel GC-rich motif (-161/-147) upstream of the Runx2 binding site was identified as a negative GRE.
  • This motif binds Egr2/Krox20 transcription factors, acting as an enhancer in osteoblasts.
  • Dexamethasone repressed the enhancer activity, and this repression was linked to decreased Egr2/Krox20 expression.

Conclusions:

  • An Egr2/Krox20-binding site functions as a glucocorticoid-repressed enhancer in the mouse OC promoter.
  • This mechanism, likely conserved in humans, contributes to glucocorticoid-induced osteoporosis by inhibiting bone formation.
  • Targeting Egr2/Krox20 may offer therapeutic strategies against glucocorticoid-induced bone loss.

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