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      Enamel and dental anomalies in latent‐transforming growth factor beta‐binding protein 3 mutant mice

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          Abstract

          Latent‐transforming growth factor beta‐binding protein 3 ( LTBP‐3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor‐ β ( TGFβ). To investigate the role of LTBP‐3 in tooth formation we performed micro‐computed tomography (micro‐ CT), histology, and scanning electron microscopy analyses of adult Ltbp3‐/‐ mice. The Ltbp3‐/‐ mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation‐stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous‐like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP‐3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGFβ signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3‐/‐ mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3 , which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes.

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          Most cited references31

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          TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation

          Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in a vast majority of cellular processes and is fundamentally important throughout life. TGF-β/BMPs have widely recognized roles in bone formation during mammalian development and exhibit versatile regulatory functions in the body. Signaling transduction by TGF-β/BMPs is specifically through both canonical Smad-dependent pathways (TGF-β/BMP ligands, receptors and Smads) and non-canonical Smad-independent signaling pathway (e.g. p38 mitogen-activated protein kinase pathway, MAPK). Following TGF-β/BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation. The coordinated activity of Runx2 and TGF-β/BMP-activated Smads is critical for formation of the skeleton. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of TGF-β/BMP signaling in bone and in the signaling networks underlying osteoblast differentiation and bone formation. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in bone from studies of genetic mouse models and human diseases caused by the disruption of TGF-β/BMP signaling. This review also highlights the different modes of cross-talk between TGF-β/BMP signaling and the signaling pathways of MAPK, Wnt, Hedgehog, Notch, and FGF in osteoblast differentiation and bone formation.
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            TGF-β – an excellent servant but a bad master

            The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.
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              BMP signaling in skeletal development.

              Mei Wan, Xu Cao (2005)
              Development of the vertebrate skeleton, a complex biological event that includes diverse processes such as formation of mesenchymal condensations at the sites of future skeletal elements, osteoblast and chondrocyte differentiation, and three dimensional patterning, is regulated by many growth factors. Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, play a pivotal role in the signaling network and are involved in nearly all processes associated with skeletal morphogenesis. BMP signals are transduced from the plasma membrane receptors to the nucleus through both Smad pathway and non-Smad pathways, and regulated by many extracellular and intercellular proteins that interact with BMPs or components of the BMP signaling pathways. To gain a better understanding of the molecular mechanisms underlying the role of BMP in early skeletal development, it is necessary to elucidate the BMP signaling transduction pathways in chondrocytes and osteoblasts. The major objective of this review was to summarize BMP signaling pathways in the context of craniofacial, axial, and limb development. In particular, this discourse will focus on recent advances of the role of different ligands, receptors, Smads, and BMP regulators in osteoblast and chondrocyte differentiation during embryonic development.
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                Author and article information

                Contributors
                agnes.bloch-zupan@unistra.fr
                Journal
                Eur J Oral Sci
                Eur. J. Oral Sci
                10.1111/(ISSN)1600-0722
                EOS
                European Journal of Oral Sciences
                John Wiley and Sons Inc. (Hoboken )
                0909-8836
                1600-0722
                13 January 2017
                February 2017
                : 125
                : 1 ( doiID: 10.1111/eos.2017.125.issue-1 )
                : 8-17
                Affiliations
                [ 1 ] Faculté de Chirurgie DentaireUniversité de Strasbourg StrasbourgFrance
                [ 2 ] CNRS UMR_7104 INSERM U964 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) Centre Européen de Recherche en Biologie et en Médecine (CERBM)Université de Strasbourg IllkirchFrance
                [ 3 ] Faculty of Dentistry, Pediatric DentistryKhon Kaen University Khon KaenThailand
                [ 4 ] Biomaterials and Bioengineering Inserm UMR1121 StrasbourgUniversité de Strasbourg StrasbourgFrance
                [ 5 ] Department of Cell BiologyNew York University Medical Center New York NYUSA
                [ 6 ] Pôle de Médecine et Chirurgie Bucco‐Dentaires Centre de Référence des Manifestations Odontologiques des Maladies RaresO Rares, Hôpitaux Universitaires de Strasbourg StrasbourgFrance
                Author notes
                [*] [* ] Agnès Bloch‐Zupan, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France

                E‐mail: agnes.bloch-zupan@ 123456unistra.fr

                Article
                EOS12328
                10.1111/eos.12328
                5260799
                28084688
                4b756d69-a97d-44c7-8d07-31fd73fdaac3
                © 2017 The Authors. Eur J Oral Sci published by John Wiley & Sons Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 07 December 2016
                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 5894
                Funding
                Funded by: Centre Européen de Recherche en Biologie et en Médecine (CERBM GIE)
                Funded by: CNRS
                Funded by: Inserm
                Funded by: University of Strasbourg
                Funded by: French Ministry of Health
                Funded by: IFRO (Institut Français pour la Recherche Odontologique)
                Funded by: National Institutes of Health
                Award ID: CA034282
                Funded by: Khon Kaen University scholarships
                Funded by: European Regional Development Fund (ERDF) of the European Union
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                eos12328
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:02.05.2017

                Dentistry
                amelogenesis,enamel,ltbp3,mouse,scanning electron microscopy
                Dentistry
                amelogenesis, enamel, ltbp3, mouse, scanning electron microscopy

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