Department of Joint Surgery and Sports Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
FASEB J. 2020 Sep;34(9):12834-12846. doi: 10.1096/fj.202000106R. Epub 2020 Aug 7.
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.
母体地塞米松可使新生儿的身长缩短。然而，地塞米松是否抑制胎儿长骨生长板的发育尚不清楚。在这里，我们发现，在接受母体地塞米松（从妊娠第 9 天至 20 天每天 0.2mg/kg.d）处理的胎儿中，胎儿股骨和生长板的长度均较短，且胎鼠生长板中的蛋白聚糖含量降低。还观察到，编码软骨细胞中蛋白聚糖生物合成关键酶的 UDP-葡萄糖脱氢酶（Ugdh）基因的表达和 H3K9 乙酰化均显著降低。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）基因表达上调。在过多外源性地塞米松处理的软骨源性大鼠骨髓基质细胞（BMSCs）中也观察到类似的变化。然而，用 RU486 拮抗 GR 并用特异性 siRNA 沉默 Hdac1 或 Sp3 均可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，其进一步直接与 Ugdh 启动子结合，并分别与 HDAC1 和 Sp3 相互作用。总之，我们的研究表明，母体地塞米松诱导了大鼠胎儿生长板软骨细胞中 GR 直接与 Ugdh 启动子结合，募集了 HDAC1 和 Sp3，诱导了 H3K9 的去乙酰化，并随后抑制了 Ugdh 基因表达。这些变化进一步导致发育中的软骨细胞中蛋白聚糖合成减少，从而破坏了生长板和胎儿长骨的发育。
