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Abstract：
Bone remodeling is vital to the maintenance of bone homeostasis and may lead to destructive skeletal diseases once the balance is disrupted. Crosstalk between Wnt and estrogen receptor (ER) signaling has been proposed in bone remodeling, but the underlying mechanism remains unclear. This study was designed to explore the effect of Wnt-ER signaling during the osteogenic differentiation of bone marrow stromal cells (BMSCs). Rat BMSCs were isolated and identified using flow cytometry and stimulated with Wnt3a. Wnt3a treatment promoted osteogenic differentiation and mineralization of the BMSCs. Meanwhile, Wnt3a enhanced the expression of ERα as well as the canonical Wnt signaling mediator β-catenin and the alternative Wnt signaling effector Yes-associated protein 1 (YAP1). Interestingly, DNA pulldown assay revealed direct binding of transcriptional enhanced associate domain 1 (TEAD1) and lymphoid enhancer binding factor 1 (LEF1), transcriptional partners of YAP1 and β-catenin, respectively, to the promoter region of ERα. In addition, inhibition of TEAD1 and LEF1 suppressed Wnt3-promoted BMSC osteogenic differentiation and blocked Wnt3a-induced ERα expression. Furthermore, an in vivo model of femoral bone defect also supported that Wnt3a facilitated bone healing in an ERα-dependent way. Together, we suggest that Wnt3a promotes the osteogenic activity of BMSCs through YAP1 and β-catenin-dependent activation of ERα, via direct binding of TEAD1 and LEF1 to the ERα promoter.
摘要：
骨重塑对于维持骨稳态至关重要，一旦平衡被破坏，可能导致破坏性的骨骼疾病。Wnt和雌激素受体（ER）信号之间的串扰已被提出在骨重建中，但潜在的机制仍不清楚。本研究旨在探讨Wnt-ER信号在骨髓基质细胞（BMSCs）成骨分化过程中的作用。使用流式细胞术分离和鉴定大鼠BMSC并用Wnt3a刺激。Wnt3a处理促进BMSCs的成骨分化和矿化。同时,Wnt3a增强ERα的表达以及典型的Wnt信号传导介质β-catenin和替代的Wnt信号传导效应Yes相关蛋白1（YAP1）。有趣的是,DNA下拉分析显示转录增强相关域1（TEAD1）和淋巴增强子结合因子1（LEF1）直接结合，YAP1和β-catenin的转录伴侣，分别,至ERα的启动子区域。此外,抑制TEAD1和LEF1抑制Wnt3促进BMSC成骨分化并阻断Wnt3a诱导的ERα表达。此外，股骨骨缺损的体内模型也支持Wnt3a以ERα依赖性方式促进骨愈合。一起,我们认为Wnt3a通过YAP1和β-catenin依赖性激活ERα促进BMSCs的成骨活性,通过TEAD1和LEF1与ERα启动子的直接结合。
