2. Academic Validation
  3. Prenatal dexamethasone exposure reduces osteoprogenitor proliferation in mice via histone modifications at the Mkp-1 gene locus

Prenatal dexamethasone exposure reduces osteoprogenitor proliferation in mice via histone modifications at the Mkp-1 gene locus

  • Commun Biol. 2024 Nov 28;7(1):1589. doi: 10.1038/s42003-024-07288-x.
Yongheng Xie # 1 2 3,  Jianwen Su # 1 2,  Mankai Yang # 1 2,  Zixian Liu 1 2,  Te Chen 1 2,  Jikun Qian 1 2,  Bin Yu 1 2,  Xianrong Zhang 4 5
Affiliations

Affiliations

  • 1 Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China.
  • 2 Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Division of Spine, Department of Orthopedic Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
  • 4 Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China. xianrongzh@smu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. xianrongzh@smu.edu.cn.
  • # Contributed equally.
PMID: 39609620 DOI: 10.1038/s42003-024-07288-x
Abstract

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.

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