Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption.
Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption.
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DOI：
10.1016/j.matbio.2016.01.002
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Foster BL
中科院分区：
文献类型：
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作者：
Xu H;Snider TN;Wimer HF;Yamada SS;Yang T;Holmbeck K;Foster BL
膜型基质金属蛋白酶 1 (MT1-MMP) 是一种跨膜锌内肽酶，可在组织发育和生理重塑过程中分解细胞外基质成分，包括多种胶原蛋白。 MT1-MMP 缺陷小鼠 (MT1-MMP−/−) 的结缔组织存在严重缺陷，例如生长受损、骨质减少、纤维化以及臼齿萌出和牙根形成明显丧失。为了明确 MT1-MMP 在牙根形成和牙齿萌出过程中的功能，我们分析了在没有 MT1-MMP 的情况下牙齿和周围组织的发育。原位杂交显示MT1-MMP在发育过程中广泛表达于与牙齿及周围结缔组织相关的细胞中。牙槽组织的多种缺陷与 MT1-MMP 的缺失有关。赫特维希上皮根鞘（HERS）的结构和功能缺陷抑制了根的形成。然而，在萌出路径的创建过程中没有发现缺陷，这表明牙齿萌出因缺乏牙槽骨建模/重塑而受到阻碍，同时牙周膜（PDL）形成和与牙槽骨的整合减少。此外，我们还发现了与 MT1-MMP 丢失相关的牙本质形成和矿化的显着缺陷。为了分离这些多重缺陷并追踪其细胞起源，在上皮和间充质中进行 MT1-MMP 的条件消融。上皮细胞中 MT1-MMP 活性选择性丧失的小鼠与野生型小鼠没有区别，重要的是，其具有正常的 HERS 结构和磨牙萌出。相比之下，在表达Osterix的间充质细胞（包括成骨细胞和成牙本质细胞）中选择性敲除MT1-MMP，重现了整体敲除的主要缺陷，包括HERS结构改变、牙根短、牙本质形成和矿化缺陷以及牙槽骨形成减少，尽管磨牙能够萌出。这些数据表明，牙间充质中的 MT1-MMP 活性，而不是上皮源性 HERS 中的活性，对于牙根的正常形成和萌出至关重要。总之，我们的研究指出，MT1-MMP 介导的基质重塑通过影响骨形成、软组织重塑和毛囊/PDL 区域的组织，在牙齿萌出中发挥着不可或缺的作用。
Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a transmembrane zinc-endopeptidase that breaks down extracellular matrix components, including several collagens, during tissue development and physiological remodeling. MT1-MMP-deficient mice (MT1-MMP−/−) feature severe defects in connective tissues, such as impaired growth, osteopenia, fibrosis, and conspicuous loss of molar tooth eruption and root formation. In order to define the functions of MT1-MMP during root formation and tooth eruption, we analyzed the development of teeth and surrounding tissues in the absence of MT1-MMP. In situ hybridization showed that MT1-MMP was widely expressed in cells associated with teeth and surrounding connective tissues during development. Multiple defects in dentoalveolar tissues were associated with loss of MT1-MMP. Root formation was inhibited by defective structure and function of Hertwig's epithelial root sheath (HERS). However, no defect was found in creation of the eruption pathway, suggesting that tooth eruption was hampered by lack of alveolar bone modeling/remodeling coincident with reduced periodontal ligament (PDL) formation and integration with the alveolar bone. Additionally, we identified a significant defect in dentin formation and mineralization associated with the loss of MT1-MMP. To segregate these multiple defects and trace their cellular origin, conditional ablation of MT1-MMP was performed in epithelia and mesenchyme. Mice featuring selective loss of MT1-MMP activity in the epithelium were indistinguishable from wild type mice, and importantly, featured a normal HERS structure and molar eruption. In contrast, selective knock-out of MT1-MMP in Osterix-expressing mesenchymal cells, including osteoblasts and odontoblasts, recapitulated major defects from the global knock-out including altered HERS structure, short roots, defective dentin formation and mineralization, and reduced alveolar bone formation, although molars were able to erupt. These data indicate that MT1-MMP activity in the dental mesenchyme, and not in epithelial-derived HERS, is essential for proper tooth root formation and eruption. In summary, our studies point to an indispensable role for MT1-MMP-mediated matrix remodeling in tooth eruption through effects on bone formation, soft tissue remodeling and organization of the follicle/PDL region.