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Glucocorticoids Hijack Runx2 to Stimulate Wif1 for Suppression of Osteoblast Growth and Differentiation

Eri Morimoto1, Meng Li2, Aysha B Khalid3

  • 1Departments of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

Journal of Cellular Physiology
|April 11, 2016
PubMed

Insights

Glucocorticoids (GCs) and Runx2 synergistically stimulate Wnt inhibitory Factor 1 (Wif1), exacerbating osteoporosis. Silencing Wif1 partially reverses GC-induced inhibition of bone formation markers and Runx2

Area of Science:

  • Molecular biology
  • Cell biology
  • Endocrinology

Background:

  • Glucocorticoid-induced osteoporosis (GIO) involves suppressed bone formation.
  • Runx2 is a key transcription factor in bone formation, and its inhibition is a mechanism in GIO.

Purpose of the Study:

  • To investigate the interplay between glucocorticoids (GCs) and Runx2 in regulating gene expression and cellular processes relevant to bone formation.
  • To identify specific genes synergistically regulated by GCs and Runx2.

Main Methods:

  • mRNA expression profiling in ST2/Rx2(dox) cells treated with doxycycline (dox) and/or dexamethasone (dex).
  • Validation of gene expression using RT-qPCR.
  • Detection of Wnt inhibitory Factor 1 (Wif1) protein.
  • Assessment of alkaline phosphatase (ALP) activity.
  • Cell proliferation assays (S-phase percentage).
  • Wif1 silencing experiments.

Main Results:

  • Dexamethasone (dex) antagonized most Runx2-driven transcription, but synergistically stimulated select genes.
  • Wnt inhibitory Factor 1 (Wif1) was identified as a gene synergistically stimulated by GCs and Runx2, with Wif1 protein detected upon co-treatment.
  • GCs inhibited Runx2-driven alkaline phosphatase (ALP) activity, an effect blunted by Wif1 silencing.
  • Runx2 induction transiently increased proliferation in ST2 cells, an effect inhibited by dex, which was partially reversed by Wif1 silencing.

Conclusions:

  • Cooperation between Runx2 and GCs stimulates Wif1, potentially thwarting compensatory Runx2 activation in GIO and exacerbating disease progression.
  • Wif1 plays a role in mediating the inhibitory effects of GCs on Runx2-driven osteogenic differentiation and proliferation.

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