Clarification of the molecular mechanisms underlying osteoclastogenesis provides us new insights into both the physiology of bone metabolism and the pathophysiology of bone diseases. Recent studies revealed that osteoclastogenic Transcription Factors (TFs) sequentially and co-operatively facilitate the expression of osteoclast genes and determine osteoclast identity. However, there are still numerous other unidentified TFs involved in osteoclastogenesis. Recently, we have identified novel osteoclastogenic TFs including Zscan10, Atf1, Nrf1, and Srebf2 by using a novel genome-wide approach, DNase-seq. However, physiological and pathological functions of these TFs in bone metabolism remain unclear although osteoclastogenesis was impaired by knockdown of these factors in primary osteoclasts. Among them, we focused on Srebp2 encoded by Srebf2, one of the master regulators of cholesterol regulation, because several studies reported a strong relationship between osteoclastogenesis and cholesterol homeostasis. To investigate the in vivo functions of Srebp2, RANKL-treated mice were administrated with an inhibitor of Srebp2, fatostatin. The mice were treated with fatostatin every day from 2 days before RANKL-injection, and the mice were sacrificed at 48 hrs after RANKL-injection. Then we performed micro-computed tomography (μCT) analysis. From the results of μCT analysis, fatostatin treatment rescued the reduction of trabecular bone volume, and trabecular number and the increase of trabecular separation in RANKL-treated mice. Bone histomorphometric analysis revealed that fatostatin treatment reduced the number of osteoclast in RANKL treated mice. Moreover, fatostatin treatment inhibited osteoclast differentiation in vitro. These results suggested that fatostatin might affect osteoclast differentiation mediating through Srebp2 inhibition and might prevent RANKL-induced bone loss in vivo. Taken together, our studies demonstrated that we succeeded in identifying Srebp2 as a novel transcription factor regulating osteoclastogenesis and inhibitors of Srebp2 might be a potential therapeutic strategy for osteoporosis. Further studies on Srebp2 functions will uncover more precise molecular mechanism underlying relationship between cholesterol homeostasis and bone metabolism.
Disclosure: The authors declared no competing interests.