Abstract：
Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.
摘要：
镍,常见的环境危害，是颅骨融合症的危险因素.然而,潜在的生物学机制仍不清楚.这里,我们发现早期镍暴露会导致小鼠颅骨融合。体外，镍促进人骨髓间充质干细胞（hMSCs）成骨分化，并通过异位成骨模型证实了其体内成骨能力。进一步的mRNA测序显示ERK1/2信号和FGFR2异常激活。FGFR2被鉴定为ERK1/2信号传导的关键调节因子。通过启动子甲基化预测和甲基化特异性PCR（MSP）测定，我们发现镍在FGFR2的启动子中诱导低甲基化，这增加了其与转录因子Sp1的结合亲和力。在怀孕和产后阶段，AZD4547通过抑制FGFR2和ERK1/2拯救镍诱导的颅骨融合。与正常人相比，颅骨融合症患者血清中的镍水平升高。进一步的逻辑和RCS分析表明，镍是颅骨融合的独立危险因素，具有非线性相关性。中介分析表明，FGFR2介导了30.13％的镍与颅骨融合风险之间的关联。总的来说，我们证明早期镍暴露会触发FGFR2的低甲基化及其与Sp1的结合，从而通过ERK1/2信号促进hMSCs的成骨分化，导致颅骨融合。
