The ER\u03b1/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells

Zhenqing Liu,Peng Deng,Tara Aghaloo,Vivian Chen,Olga Bezouglaia,Jin Sook Suh,Christine Hong,Chang-Ryul Lee,Min Lee,Hye-Lim Lee,Mojan Mirnia,Zhong-Kai Cui,Michael Zhou,Reuben H Kim,Cun-Yu Wang

doi:10.1038/s41413-021-00171-z

Abstract

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. 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). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. 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. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. 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. 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. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

Highlights

Osteoporosis is a systemic disorder characterized by skeletal microarchitectural deterioration and reduced bone mass leading to fracture risks
KDM6B knockdown was shown to inhibit BMP2 and HOXC6 expression in dental mesenchymal stromal cells (DMSCs) through epigenetic modifications of histone methylation at the promoter regions of BMP2 and HOXC6, suggesting that KDM6B is vital for osteogenic differentiation.[25]
Since our in vitro findings suggested that KDM6B plays a critical role in E2-mediated DMSC osteogenesis, we further evaluated whether KDM6B is required for in vivo bone repair using a calvarial defect mouse model

Summary

ARTICLE OPEN

Zhenqing Liu[1], Hye-Lim Lee[2], Jin Sook Suh[3], Peng Deng[1], Chang-Ryul Lee[4], Olga Bezouglaia[5], Mojan Mirnia[6], Vivian Chen[4], Michael Zhou[6], Zhong-Kai Cui 7, Reuben H. KDM6B epigenetically regulates E2-mediated BMP2 and HOXC6 gene expression in DMSCs by demethylating H3K27me[3] marks The BMP2 and HOXC6 genes are known to be critical players in osteogenic differentiation.[25,42,43] KDM6B knockdown was shown to inhibit BMP2 and HOXC6 expression in DMSCs through epigenetic modifications of histone methylation at the promoter regions of BMP2 and HOXC6, suggesting that KDM6B is vital for osteogenic differentiation.[25] We explored the effects of estrogen on BMP2 and HOXC6 expression and found that E2 treatment significantly upregulated BMP2 and HOXC6 expression levels (Fig. 3a). These results show that E2-mediated bone repair is KDM6B dependent

DISCUSSION

Findings

Cell isolation and culture