Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium

Rakian, Audrey; Wu, Yang; Gluhak-Heinrich, Jelica; Cui, Yong; Harris, Marie A.; Villarreal, Demitri; Feng, Jerry Q.; MacDougall, Mary; Harris, S. E.

doi:10.1038/ijos.2013.41

Cited by 61 publications

(60 citation statements)

References 29 publications

(56 reference statements)

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“…The Osterix ( Osx )- Cre line has been used to selectively delete floxed alleles in committed osteoblasts and odontoblasts [30, 31], though the spatiotemporal expression of Osx in the wider periodontium has not been completely resolved [32-34]. While the Osx-Cre transgene has been reported to cause delayed or defective skeletal and craniofacial mineralization resulting from Osterix loss-of-function [35-37], studies including analysis of molar teeth have not identified similar dental defects [30, 38, 39].…”

Section: Resultsmentioning

confidence: 99%

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Snider

Wimer

et al. 2016

Matrix Biology

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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.

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Section: Resultsmentioning

confidence: 99%

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Snider

Wimer

et al. 2016

Matrix Biology

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“…Some models, such as Osr2-Cre;Smad4 fl/fl and K14-Cre;Smad4 fl/fl (Huang et al, 2010), show phenotypes in early stages of tooth development, but it is hard to determine whether the root defect is secondary to the crown defect. Other models, including OC-Cre (Bae et al, 2013b;Gao et al, 2009;Kim et al, 2013;Zhang et al, 2013), Col1a1-Cre (Kim et al, 2012) and Sp7-Cre (Rakian et al, 2013;Wang et al, 2013), take effect too late, only targeting differentiated cells. Here, we used the Gli1-CreERT/loxP system to target the early progenitor cells for root development.…”

Section: Discussionmentioning

confidence: 99%

An Nfic-hedgehog signaling cascade regulates tooth root development

Liu

Feng

et al. 2015

Development

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Coordination between the Hertwig's epithelial root sheath (HERS) and apical papilla (AP) is crucial for proper tooth root development. The hedgehog (Hh) signaling pathway and Nfic are both involved in tooth root development; however, their relationship has yet to be elucidated. Here, we establish a timecourse of mouse molar root development by histological staining of sections, and we demonstrate that Hh signaling is active before and during root development in the AP and HERS using Gli1 reporter mice. The proper pattern of Hh signaling activity in the AP is crucial for the proliferation of dental mesenchymal cells, because either inhibition with Hh inhibitors or constitutive activation of Hh signaling activity in transgenic mice leads to decreased proliferation in the AP and shorter roots. Moreover, Hh activity is elevated in Nfic −/− mice, a root defect model, whereas RNA sequencing and in situ hybridization show that the Hh attenuator Hhip is downregulated. ChIP and RNAscope analyses suggest that Nfic binds to the promoter region of Hhip. Treatment of Nfic −/− mice with Hh inhibitor partially restores cell proliferation, AP growth and root development. Taken together, our results demonstrate that an NficHhip-Hh signaling pathway is crucial for apical papilla growth and proper root formation. This discovery provides insight into the molecular mechanisms regulating tooth root development.

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“…4). Specifically, deletion of Bmp2 in osterixpositive mesenchymal progenitor cells causes abnormal odontoblast differentiation and short roots (Rakian et al, 2013). Moreover, restriction of Bmp4 expression in the dental mesenchyme by Ring proteins, which contain a characteristic zinc-finger domain that mediates protein-protein interactions, affects odontoblast differentiation and root formation (Lapthanasupkul et al, 2012).…”

Section: Bmp/tgfβ Signalingmentioning

confidence: 99%

Cellular and molecular mechanisms of tooth root development

2017

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The tooth root is an integral, functionally important part of our dentition. The formation of a functional root depends on epithelialmesenchymal interactions and integration of the root with the jaw bone, blood supply and nerve innervations. The root development process therefore offers an attractive model for investigating organogenesis. Understanding how roots develop and how they can be bioengineered is also of great interest in the field of regenerative medicine. Here, we discuss recent advances in understanding the cellular and molecular mechanisms underlying tooth root formation. We review the function of cellular structure and components such as Hertwig's epithelial root sheath, cranial neural crest cells and stem cells residing in developing and adult teeth. We also highlight how complex signaling networks together with multiple transcription factors mediate tissue-tissue interactions that guide root development. Finally, we discuss the possible role of stem cells in establishing the crown-to-root transition, and provide an overview of root malformations and diseases in humans.

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Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium

Cited by 61 publications

References 29 publications

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

An Nfic-hedgehog signaling cascade regulates tooth root development

Cellular and molecular mechanisms of tooth root development

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