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J. Biol. Chem., Vol. 277, Issue 4, 2695-2701, January 25, 2002
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From the The transcription factor RUNX2
(Cbfa1/AML3/Pebp2
Expression of the Osteoblast Differentiation Factor RUNX2
(Cbfa1/AML3/Pebp2
A) Is Inhibited by Tumor Necrosis
Factor-*
,,,,¶
Division of Endocrinology and Metabolism,
Emory University School of Medicine and Atlanta Veterans Affairs
Medical Center, Atlanta, Georgia 30033 and the § Department
of Cell Biology, University of Massachusetts Medical School,
Worcester, Massachusetts 01655
A) is a critical regulator of osteoblast
differentiation. We investigated the effect of the inflammatory
cytokine tumor necrosis factor (TNF) on the expression of RUNX2
because TNF is known to inhibit differentiation of osteoblasts from
pluripotent progenitor cells. TNF treatment of fetal calvaria precursor
cells or MC3T3-E1 clonal pre-osteoblastic cells caused a
dose-dependent suppression of RUNX2 steady state mRNA
as measured by reverse transcription-PCR. The IC50
for TNF inhibition was 0.6 ng/ml. TNF suppression of RUNX2 mRNA was
confirmed using Northern analysis. The effect of TNF was studied using
isoform-specific primers that flanked unique regions of two major RUNX2
isoforms. TNF suppressed expression of the mRNA coding for the
shorter MRIPV isoform by >90% while inhibiting expression of the
mRNA for the longer MASNS isoform by 50%. RUNX2 nuclear content
was evaluated by electrophoretic mobility shift assay using a rat
osteocalcin promoter binding sequence as probe and by Western analysis.
TNF reduced nuclear RUNX2 protein. Inhibition of new protein synthesis
with cycloheximide failed to prevent TNF inhibition of RUNX2 mRNA,
suggesting that a newly translated protein did not mediate the TNF
effect. RUNX2 mRNA half-life was 1.8 h and reduced to 0.9 h by TNF. The effect of TNF on RUNX2 gene transcription was evaluated
using a 0.6-kb RUNX2 promoter-luciferase reporter in MC3T3-E1 cells.
TNF caused a dose-dependent inhibition of transcription to
50% of control values. The inhibitory effect of TNF was preserved with
deletions to nucleotide 
108 upstream of the translational start site;
however, localization downstream of nucleotide 108 was obscured by
loss of basal activity. Our results indicate that TNF regulates RUNX2 expression at multiple levels including destabilization of mRNA and
suppression of transcription. The disproportionate inhibition of RUNX2
nuclear protein suggests that additional post-transcriptional mechanisms may be occurring. Suppression of RUNX2 by TNF may decrease osteoblast differentiation and inhibit bone formation in TNF excess states.
*
This work was supported by National Institutes of Health
Grant R01 AR46452-01 and a Department of Veterans Affairs Merit Review grant (both to M. S. N.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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