Little is known about the molecular mechanisms underlying the interaction between Sclerostin (SOST) and estrogen, showing an inverse relation in clinical data. Therefore, we investigated mechanisms by which estrogen modulates Sost expression at human osteoblastic cell level in association with BMP-2 signaling, which is a potential route of SOST induction. BMP-2 significantly induced SOST expression, which is suppressed by 17β-estradiol (E2) in human mesenchymal stromal cells (hMSCs) and mandible-derived osteoblasts from female donors, despite non-effect of E2 alone on SOST expression. E2 increased transcriptional activity of β-catenin/TCF/LEF responsive vector, which is suppressed by the combined treatment of BMP-2 and E2 in hMSCs. Either estrogen receptor (ER)α antagonist or silencing of ERα gene did counteract the suppressive effect of E2 on SOST induction by BMP-2, while it had no effect on the activity of BMP-2 alone BMP-2. However, E2 had non-effect on the transcriptional activity of Smad4, which was but dependent of BMP-2. SOST expression pattern from human osteoblasts was in particular correlated with the relative ratio of RANKL to OPG expression. Taken together, these findings showed that estrogen negatively modulates SOST expression coupled with BMP-2 signaling, which involve Wnt pathway via ERα and β-catenin, providing insight into how estrogen is anabolic to bone at the level of osteoblastic cells.
Keywords: Estrogen, sclerostin, BMP-2, human mesenchymal stromal cells, human osteoblasts, Wnt pathway, estrogen receptor α, RANKL/OPG
17 May 2014 - 20 May 2014