The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells

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.

Dysregulation of histone modifications in bone marrow mesenchymal stem cells during skeletal ageing: roles and therapeutic prospects

“…KDM6B demethylates H3K27me3 to promote the expression of Bmp2 , Bmp4 , Runx2 and Hoxc6-1 and induce osteogenic commitment of BM-MSCs, thus elevating bone mass in OVX and aged mice [ 54 , 55 ]. Similar results have also been demonstrated in human dental MSCs [ 56 ]. KDM7A (also called KIAA1718 or JHDM1D) has demethylase activity for H3K27me1/me2 and H3K9me1/me2 [ 57 ], and can enhance adipogenesis and weaken osteogenesis by demethylating H3K9me2 and H3K27me2 on the promoters of Sfrp1 and C/ebpα in mouse primary BM-MSCs and ST2 cells [ 58 ].…”

Dual-Targeted Nanodiscs Revealing the Cross-Talk between Osteogenic Differentiation of Mesenchymal Stem Cells and Macrophages

“…It has been reported that lysine-specific demethylase 4B (KDM4B) and lysine-specific demethylase 6B (KDM6B) are most strongly induced by bone morphogenetic protein (BMP)-4/7 and promote osteogenic differentiation of human MSCs . KDM6B is recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 markers and activation of the transcription of BMP2 and HOXC6 . Jmjd3 (KDM6B)-mediated H3K27 demethylation is considered a crucial factor for regulating M2 macrophage development, leading to anti-helminth host responses .…”

“… 9 KDM6B is recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 markers and activation of the transcription of BMP2 and HOXC6. 10 Jmjd3 (KDM6B)-mediated H3K27 demethylation is considered a crucial factor for regulating M2 macrophage development, leading to anti-helminth host responses. 11 In addition, macrophages are well known to play a pivotal role in the induction of bone mesenchymal stem cells toward osteoblastic fate.…”

KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties

“…This favors adipogenic and inhibits osteogenic differentiation potential of bone marrowmesenchymal stromal cells (BM-MSCs). Conversely, the H3K27me3 demethylases, lysine demethylase 6A (KDM6A) (also known as UTX) and lysine demethylase 6B (KDM6B) (JMJD3) inhibit adipogenesis and promote osteogenesis, suggesting a key role for H3K27-centered epigenetic switch in stromal cell fate specification (21)(22)(23)(24). KDM6B is widely known for its role during inflammatory response and harbors NF-κB binding sites in its promoter (25,26).…”