Xu H, Snider T N, Wimer H F, Yamada S S, Yang T, Holmbeck K, Foster B L
Department of Pediatric Dentistry, Peking University and School and Hospital of Stomatology, Beijing, China.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
Matrix Biol. 2016 May-Jul;52-54:266-283. doi: 10.1016/j.matbio.2016.01.002. Epub 2016 Jan 15.
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.
膜型基质金属蛋白酶1（MT1-MMP）是一种跨膜锌内肽酶，在组织发育和生理重塑过程中可分解细胞外基质成分，包括多种胶原蛋白。MT1-MMP基因敲除小鼠（MT1-MMP(-/-)）在结缔组织中存在严重缺陷，如生长受损、骨质减少、纤维化，以及磨牙萌出和牙根形成明显缺失。为了明确MT1-MMP在牙根形成和牙齿萌出过程中的功能，我们分析了在缺乏MT1-MMP的情况下牙齿及周围组织的发育情况。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）结构和功能缺陷抑制了牙根形成。然而，在萌出道的形成过程中未发现缺陷，这表明牙齿萌出受阻是由于牙槽骨建模/重塑缺乏，同时牙周韧带（PDL）形成减少以及与牙槽骨的整合受损。此外，我们发现与MT1-MMP缺失相关的牙本质形成和矿化存在显著缺陷。为了区分这些多种缺陷并追踪其细胞起源，我们在上皮和间充质中进行了MT1-MMP的条件性消融。上皮中MT1-MMP活性选择性缺失的小鼠与野生型小鼠无异，重要的是，其HERS结构正常且磨牙萌出正常。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，重现了整体敲除后的主要缺陷，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，牙齿间充质而非上皮来源的HERS中的MT1-MMP活性对于正常的牙根形成和萌出至关重要。总之，我们的研究表明MT1-MMP介导的基质重塑通过影响骨形成、软组织重塑以及滤泡/PDL区域的组织化，在牙齿萌出中发挥不可或缺的作用。
