title: Fatostatin, an SREBP inhibitor, prevented RANKL-induced bone loss by suppression of osteoclast differentiation.
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.
authors: Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Ehime, Japan.
authors: Kazuki
authors: K
authors: Inoue
authors: Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Ehime, Japan; Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime, Japan. Electronic address: y-imai@m.ehime-u.ac.jp.
authors: Yuuki
authors: Y
authors: Imai
keywords: DNase-seq; Fatostatin; Micro CT; Osteoclast; Srebf2