Estrogen promotes osteogenesis via YAP1-driven activation of ERα orchestrated through TEAD1 binding to the ERα promoter.

Bone remodeling is a dynamic process that is essential for maintaining skeletal integrity and homeostasis. Although crosstalk between Yes-associated protein 1 (YAP1) and estrogen receptor alpha (ERα) has been implicated in bone biology, the mechanism by which these pathways cooperate during osteogenesis remains incompletely defined. Here, primary mouse bone marrow stromal cells (BMSCs) were isolated and characterized, and then stimulated with 17β-estradiol (E2). E2 significantly enhanced osteogenic differentiation and increased the expression of ERα, YAP1, and osteogenic markers. Genetic silencing or pharmacological inhibition of YAP1 attenuated E2-induced osteogenesis and reduced ERα expression, indicating that YAP1 is required for the osteogenic response to E2. Conventional chromatin immunoprecipitation (ChIP)-PCR followed by agarose gel electrophoresis provided qualitative evidence that TEAD1 associates with the ERα promoter, and this association appeared stronger after E2 treatment but weaker after YAP1 knockdown. In vivo, E2 and the YAP activator XMU-MP-1 improved bone parameters in ovariectomized mice, and combined treatment showed the strongest rescue effect. Collectively, these data support a model in which E2 promotes BMSC osteogenesis, at least in part, through a YAP1/TEAD1-dependent increase in ERα expression. Because the ChIP assay used here was qualitative and reciprocal regulation of YAP1 by ERα was not directly tested, further quantitative and bidirectional mechanistic studies are warranted.