TGF-β3-induced palatogenesis requires matrix metalloproteinases
TGF-β3-induced palatogenesis requires matrix metalloproteinases
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DOI：
10.1091/mbc.12.5.1457
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发表时间：
2001-05-01
影响因子：
3.3
通讯作者：
Kaartinen, V
中科院分区：
文献类型：
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作者：
Blavier, L;Lazaryev, A;Kaartinen, V
唇腭裂综合征是人类最常见的先天性畸形之一。哺乳动物的腭裂发生是一个复杂的过程，包括高度调控的腭部上皮细胞和间充质细胞之间的相互作用，以保证腭架的正确定位，细胞外基质(ECM)的重塑，以及随后的腭架融合。在此，我们发现几种基质金属蛋白酶(MMPs)，包括细胞膜相关的基质金属蛋白酶(MT1-MMPs)和金属蛋白酶组织抑制因子-2(TIMP-2)在内侧边缘上皮(MEE)中高表达。基质金属蛋白酶-13在胎盘间质及邻近间充质中均有表达，而明胶酶A(明胶酶A)在癌旁间充质细胞中有表达。转化生长因子(TGF)-β3缺陷小鼠患有继发性腭裂，中线完全缺乏TIMP-2，表达显著降低的基质金属蛋白酶-13和轻微降低的基质金属蛋白酶-2的水平。与此相一致的是，转化生长因子-β3可强烈诱导腭部成纤维细胞表达基质金属蛋白酶-13。最后，从腭架上进行灌流。在MMPs合成抑制剂或过量TIMP-2存在下培养的野生型小鼠胚胎无法融合，MEE细胞不能转分化，表现出转化生长因子-β3缺陷小鼠的缺陷。我们的观察首次表明，基质金属蛋白酶对细胞外基质的蛋白降解是腭裂融合的必要步骤。
Cleft lip and palate syndromes are among the most common congenital malformations in humans. Mammalian palatogenesis is a complex process involving highly regulated interactions between epithelial and mesenchymal cells of the palate to permit correct positioning of the palatal shelves, the remodeling of the extracellular matrix (ECM), and subsequent fusion of the palatal shelves. Here we show that several matrix metalloproteinases (MMPs), including a cell membrane-associated MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were highly expressed by the medial edge epithelium (MEE). MMP-13 was expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A (MMP-2) was expressed by mesenchymal cells neighboring the MEE. Transforming growth factor (TGF)-beta3-deficient mice, which suffer from clefting of the secondary palate, showed complete absence of TIMP-2 in the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-beta3 in palatal fibroblasts. Finally, palatal shelves from prefusion. wild-type mouse embryos cultured in the presence of a synthetic inhibitor of MMPs or excess of TIMP-2 failed to fuse and MEE cells did not transdifferentiate, phenocopying the defect of the TGF-beta3-deficient mice. Our observations indicate for the first time that the proteolytic degradation of the ECM by MMPs is a necessary step for palatal fusion.