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Prenatal dexamethasone exposure reduces osteoprogenitor proliferation in mice via histone modifications at the Mkp-1
Yongheng Xie1,2,3, Jianwen Su1,2, Mankai Yang1,2
1Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China.
Insights
Prenatal dexamethasone exposure (PDE) impairs fetal osteoprogenitor proliferation and bone development by altering epigenetic modifications. Restoring histone methylation balance mitigates these detrimental effects on offspring bone growth.
Area of Science:
- Epigenetics
- Developmental Biology
- Endocrinology
Background:
- Prenatal dexamethasone exposure (PDE) is known to cause long-term bone development issues.
- The precise molecular mechanisms underlying PDE's effects on bone are not fully understood.
Purpose of the Study:
- To investigate the epigenetic mechanisms by which PDE affects osteoprogenitor proliferation and long bone development.
- To explore potential therapeutic interventions to counteract PDE's negative impacts.
Main Methods:
- Assessing bone mass, osteoblast counts, and osteoprogenitor proliferation in PDE offspring.
- Analyzing MKP-1 expression and histone modifications (H3K9me2, H3K27me3) at the Mkp-1 gene locus.
- Evaluating the effects of PFI-90 and GSK-J4 treatments on MAPK signaling and osteoprogenitor function in PDE-exposed models.
Main Results:
- PDE offspring showed reduced bone mass, fewer osteoblasts, and diminished osteoprogenitor proliferation.
- PDE increased MKP-1 expression by decreasing H3K9me2 and H3K27me3 at the Mkp-1 gene locus.
- Treatments with PFI-90 or GSK-J4 restored histone methylation balance, blocked PDE's inhibitory effects on MAPK signaling, and improved osteoprogenitor proliferation and bone development.
Conclusions:
- PDE disrupts fetal osteoprogenitor proliferation and long bone growth through an epigenetic mechanism involving MKP-1 upregulation via suppressed histone methylation.
- Restoring histone methylation balance presents a viable strategy to mitigate the adverse skeletal consequences of prenatal dexamethasone exposure.
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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