Maternal dexamethasone decreases the body length of the newborn. However, whether dexamethasone inhibits the development of the growth plate of the fetal long bone is still unknown. Here, we found that lengths of fetal femur and growth plate were both shorter in the fetuses with maternal dexamethasone (0.2 mg/kg.d from gestation day 9 to 20), with a decreased proteoglycan content of the growth plate in the fetal rat. Notable decreases in both the gene expression and H3K9 acetylation of UDP‐glucose dehydrogenase (Ugdh) gene, which codes a key enzyme in the proteoglycan biosynthesis in the chondrocyte, were also observed. Meanwhile, up‐regulation of glucocorticoid receptor (GR), specific protein 3 (Sp3), and histone deacetylase 1 (Hdac1) gene expression were detected in the fetal growth plate. Similar changes were also observed in the chondrogenic rat bone marrow stromal cells (BMSCs) with excessive exogenous dexamethasone. However, antagonizing GR with RU486 and silencing Hdac1 or Sp3 with specific siRNAs could all stimulate the H3K9 acetylation and gene expression of Ugdh previously inhibited by dexamethasone. Meanwhile, dexamethasone also induced the nuclear translocation of GR, which further directly bound to the Ugdh promoter and interacted with HDAC1 and Sp3, respectively. Collectively, our study revealed that maternal dexamethasone induced the direct binding of GR to the Ugdh promoter of the chondrocyte in the rat fetal growth plate, which recruited HDAC1 and Sp3, induced deacetylation of the H3K9, and subsequently inhibited Ugdh gene expression. Such changes further led to attenuated proteoglycan synthesis in the developing chondrocyte and therefore disrupted the development of growth plate and fetal long bone.

中文翻译：

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GR/Sp3/HDAC1/UGDH 信号参与母体地塞米松诱导的大鼠胎儿生长板发育不良

母体地塞米松减少新生儿的体长。然而，地塞米松是否抑制胎儿长骨生长板的发育仍是未知数。在这里，我们发现母体地塞米松（0.2 mg/kg.d，从妊娠第 9 天到第 20 天）的胎儿股骨和生长板的长度均较短，胎鼠生长板的蛋白多糖含量降低。还观察到 UDP-葡萄糖脱氢酶 (Ugdh) 基因的基因表达和 H3K9 乙酰化显着降低，该基因编码软骨细胞中蛋白多糖生物合成的关键酶。同时，在胎儿生长板中检测到糖皮质激素受体 (GR)、特异性蛋白 3 (Sp3) 和组蛋白去乙酰化酶 1 (Hdac1) 基因表达的上调。在外源性地塞米松过量的成软骨大鼠骨髓基质细胞 (BMSC) 中也观察到类似的变化。然而，用 RU486 拮抗 GR 并用特定的 siRNA 使 Hdac1 或 Sp3 沉默都可以刺激先前被地塞米松抑制的 Ugdh 的 H3K9 乙酰化和基因表达。同时，地塞米松还诱导了 GR 的核转位，GR 进一步直接与 Ugdh 启动子结合并分别与 HDAC1 和 Sp3 相互作用。总的来说，我们的研究表明，母体地塞米松诱导 GR 与大鼠胎儿生长板中软骨细胞的 Ugdh 启动子直接结合，募集 HDAC1 和 Sp3，诱导 H3K9 的脱乙酰化，随后抑制 Ugdh 基因表达。