Rosiglitazone suppresses RANKL-induced NFATc1 autoamplification by disrupting the physical interaction between NFATc1 and PPARγ.

Abstract:

:Receptor activator of nuclear factor-κB ligand (RANKL) is required for initiation of osteoclastogenesis, with the signaling pathway including the NF-kB, c-Fos, and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) transcription factors. Because NFATc1 expression is autoamplified, we investigated the molecular mechanism by which peroxisome proliferator-activated receptor gamma (PPARγ) activation by the thiazolidinedione drug rosiglitazone decreases NFATc1 expression during RANKL stimulation. Western blotting demonstrated that rosiglitazone attenuated the increase in NFATc1 protein level induced by RANKL without affecting that of PPARγ. Immunofluorescence data indicated that rosiglitazone tended to suppress RANKL-induced NFATc1 nuclear translocation, partly by reducing calcineurin activity, as reflected by the observed decrease in nuclear NFATc1 abundance. On coimmunoprecipitation, the intensity of the physical interaction between NFATc1 and PPARγ was unexpectedly higher in the RANKL-stimulated group than in the control, but rosiglitazone reduced this to basal levels. Furthermore, RANKL failed to elevate mRNA expression of NFATc1 after PPARγ knockdown. ChIP assay indicated that rosiglitazone significantly reduced the binding of NFATc1 to its own promoter despite RANKL stimulation. These findings suggest that PPARγ activation by rosiglitazone blocks NFATc1 from binding to its own promoter, thereby reducing RANKL-induced NFATc1 autoamplification.

journal_name

FEBS Open Bio

journal_title

FEBS open bio

authors

Park KL,Oh DG,Kim YO,Song KS,Ahn DW

doi

10.1002/2211-5463.12513

subject

Has Abstract

pub_date

2018-09-10 00:00:00

pages

1584-1593

issue

10

issn

2211-5463

pii

FEB412513

journal_volume

8

pub_type

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