Fatostatin, an SREBP inhibitor, prevented RANKL-induced bone loss by suppression of osteoclast differentiation

https://doi.org/10.1016/j.bbadis.2015.08.018Get rights and content
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Highlights

  • Knockdown or inhibition of SREBP2 in vitro impaired osteoclast differentiation.

  • Treatment with fatostatin, an SREBP inhibitor, prevented rapid RANKL-induced bone loss in mice.

Abstract

Osteoclast differentiation is associated with both normal bone homeostasis and pathological bone diseases such as osteoporosis. Several transcription factors can regulate osteoclast differentiation, including c-fos and Nfatc1. Using genome-wide DNase-seq analysis, we found a novel transcription factor, SREBP2, that participates in osteoclast differentiation in vitro. Here, we asked whether SREBP2 actually plays a role in controlling bone metabolism in vivo. To answer this question, RAW264 cells, primary cultured osteoclasts and the mouse RANKL-induced bone loss model were treated with fatostatin, a small molecule inhibitor specific for the activation of SREBP. When cells were treated with fatostatin, osteoclast differentiation was impaired. Similar results were obtained following treatment with siRNA for Srebf2, the gene coding for SREBP2. In vivo, μCT analyses showed that fatostatin treatment preserved bone mass and structure in the proximal tibial trabecular bone in the mouse RANKL-induced bone loss model. In addition, bone histomorphometric analysis revealed that the protection of bone mass by fatostatin might have been achieved by suppression of RANKL-mediated osteoclast differentiation. These results indicated that the novel transcription factor SREBP2 physiologically functions in osteoclast differentiation in vivo and might be a possible therapeutic target for bone diseases.

Abbreviations

SREBP
sterol regulatory element binding protein
RANKL
receptor activator of nuclear factor kappa B ligand
M-CSF
macrophage colony-stimulating factor
TRAP
tartrate-resistant acid phosphatase
CtsK
Cathepsin K
LdlR
low-density lipoprotein receptor

Keywords

Osteoclast
Fatostatin
DNase-seq
Srebf2
Micro CT

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