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3 However, severe adverse effects of antiresorptive agents, including atypical femur fracture or medication-related osteonecrosis of the jaw, have been reported, causing a decline in clinical use.
2 Antiresorptive agents such as bisphosphonates or denosumab are commonly used as treatment options for postmenopausal women with increased fracture risk. 1 Estrogen deficiency in postmenopausal women particularly aggravates skeletal fragility it is estimated that a 50-year-old Caucasian woman has a 50% risk of skeletal fracture. The disease is multifactorial and caused by an imbalance between bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. Osteoporosis is a systemic disorder characterized by skeletal microarchitectural deterioration and reduced bone mass leading to fracture risks. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen’s pro-osteogenic effect was dependent on KDM6B in vivo. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs).
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