Glucocorticoids alter craniofacial development and increase expression and activity of matrix metalloproteinases in developing zebrafish (Danio rerio)
Glucocorticoids alter craniofacial development and increase expression and activity of matrix metalloproteinases in developing zebrafish (Danio rerio)
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DOI：
10.1093/toxsci/kfn010
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发表时间：
2008-04-01
影响因子：
3.8
通讯作者：
White, Lori A.
中科院分区：
文献类型：
--
作者：
Hillegass, Jedd M.;Villano, Caren M.;White, Lori A.
虽然短期糖皮质激素治疗仍被用于降低胎儿死亡率、呼吸窘迫综合征和早产儿脑室内出血，但长期使用糖皮质激素可观察到致畸效应。然而，糖皮质激素诱导致畸的机制尚不清楚。我们假设糖皮质激素诱导的畸胎症是通过糖皮质激素受体（GR）介导的，其结果是改变基质金属蛋白酶（MMPs）的表达和活性。在胚胎发生过程中，细胞外基质的降解是一个严格调控的过程，以允许适当的细胞迁移和组织组织，这需要适当的时间和空间表达和MMPs的活性。研究表明，在多种模型系统中，糖皮质激素可以抑制或诱导MMP基因的表达。以斑马鱼（Danio rerio）为发育模型，本文提供的数据表明，胚胎暴露于糖皮质激素地塞米松或氢化可的松中，在受精后72小时（hpf），两种明胶酶MMP-2（类似1.5倍）和MMP-9（7.6- 9.0倍）的表达增加。此外，糖皮质激素治疗后，明胶酶活性在72 hpf时增加了约三倍，并且还观察到颅面形态发生的变化。将每种糖皮质激素与GR拮抗剂RU486共同处理斑马鱼胚胎，糖皮质激素诱导的MMP表达（减少52-84%）和活性（减少41-94%）的增加均有所减弱。此外，糖皮质激素暴露后观察到的颅面异常表型在RU486共治疗后较轻。这些研究表明，在胚胎斑马鱼中，地塞米松和氢化可的松改变了MMP-2和-9的表达和活性，并表明这些增加可能是通过GR介导的。
Teratogenic effects are observed following long-term administration of glucocorticoids, although short-term glucocorticoid therapy is still utilized to reduce fetal mortality, respiratory distress syndrome, and intraventricular hemorrhage in preterm infants. However, the mechanism of glucocorticoid-induced teratogenicity is unknown. We hypothesize that glucocorticoid-induced teratogenesis is mediated through the glucocorticoid receptor (GR) and results from altering the expression and activity of the matrix metalloproteinases (MMPs). During embryogenesis, degradation of the extracellular matrix to allow for proper cellular migration and tissue organization is a tightly regulated process requiring appropriate temporal and spatial expression and activity of the MMPs. Studies have demonstrated that MMP gene expression can be either inhibited or induced by glucocorticoids in a variety of model systems. Using the zebrafish (Danio rerio) as a model of development, the data presented here demonstrate that embryonic exposure to the glucocorticoids dexamethasone or hydrocortisone increased expression of two gelatinases, MMP-2 (similar to 1.5-fold) and MMP-9 (7.6- to 9.0-fold), at 72 h postfertilization (hpf). Further, gelatinase activity was increased approximately threefold at 72 hpf following glucocorticoid treatment, and changes in craniofacial morphogenesis were also observed. Cotreatment of zebrafish embryos with each glucocorticoid and the GR antagonist RU486 resulted in attenuation of glucocorticoid-induced increases in MMP expression (52-84% decrease) and activity (41-94% decrease). Furthermore, the abnormal craniofacial phenotype observed following glucocorticoid exposure was less severe following RU486 cotreatment. These studies demonstrate that in the embryonic zebrafish, dexamethasone, and hydrocortisone alter expression and activity of MMP-2 and -9, and suggest that these increases may be mediated through the GR.