Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China.
Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Commun Biol. 2024 Nov 28;7(1):1589. doi: 10.1038/s42003-024-07288-x.
Prenatal dexamethasone exposure (PDE) has long-term consequences in bone development, though the underlying mechanisms remain unclear. Our results show that PDE offspring exhibit reduced bone mass, fewer osteoblasts and diminished osteoprogenitors proliferation. Further analyses show that PDE increases MKP-1 expression, while decreasing H3 lysine 9 dimethylation (H3K9me2) and H3 lysine 27 trimethylation (H3K27me3) at the Mkp-1 gene locus. Mechanistically, dexamethasone suppresses osteoprogenitors proliferation by upregulating MKP-1 expression, notably through the inhibition of H3K9me2 and H3K27me3 modifications, which promote demethylation and transcriptional activation of the Mkp-1 gene. Importantly, restoring histone methylation balance with PFI-90 or GSK-J4 treatment blocks the inhibitory effects of PDE on MAPK signaling in osteoprogenitors, and mitigates the detrimental impact of PDE on osteoprogenitor proliferation and bone development in the offspring. This study provides new insights into the epigenetic mechanism by which PDE disrupts long-term programming of fetal osteoprogenitor proliferation, ultimately impairing long bone growth in offspring.
产前地塞米松暴露（PDE）对骨骼发育有长期影响，但潜在机制尚不清楚。我们的结果表明，PDE 后代表现出骨量减少、成骨细胞减少和骨祖细胞增殖减少。进一步的分析表明，PDE 增加了 MKP-1 的表达，同时降低了 Mkp-1 基因座上的 H3 赖氨酸 9 二甲基化（H3K9me2）和 H3 赖氨酸 27 三甲基化（H3K27me3）。从机制上讲，地塞米松通过上调 MKP-1 的表达来抑制骨祖细胞的增殖，特别是通过抑制 H3K9me2 和 H3K27me3 修饰，促进 Mkp-1 基因的去甲基化和转录激活。重要的是，用 PFI-90 或 GSK-J4 治疗恢复组蛋白甲基化平衡可阻断 PDE 对骨祖细胞中 MAPK 信号的抑制作用，并减轻 PDE 对后代骨祖细胞增殖和骨发育的有害影响。这项研究为 PDE 破坏胎儿骨祖细胞增殖的长期编程的表观遗传机制提供了新的见解，最终损害了后代长骨的生长。
