New Insights Into the Functions of Enamel Matrices in Calcified Tissues
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Japanese Dental Science Review (2014) 50, 47—54 Available online at www.sciencedirect.com ScienceDirect jo urnal homepage: www.elsevier.com/locate/jdsr Review Article New insights into the functions of enamel matrices in calcified tissues a, a a Satoshi Fukumoto *, Takashi Nakamura , Aya Yamada , a a b a Makiko Arakaki , Kan Saito , Juan Xu , Emiko Fukumoto , b Yoshihiko Yamada a Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan b Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, Bethesda, MD 20892, USA Received 5 July 2013; received in revised form 27 December 2013; accepted 8 January 2014 KEYWORDS Summary Ameloblasts secrete enamel matrix proteins, including amelogenin, ameloblastin, enamelin, amelotin, and Apin/odontogenic ameloblast-associated protein (Apin/ODAM). Ame- Enamel matrix; Amelogenin; logenin is the major protein component of the enamel matrix. Amelogenin, ameloblastin, and Ameloblastin; enamelin are expressed during the secretory stage of ameloblast, while amelotin and Apin/ODAM Enamelin; are expressed during the maturation. Amelogenin and ameloblastin are also expressed in Amelotin; osteoblasts, and they regulate bone formation. In addition, recent studies show the importance Odontogenic of protein—protein interactions between enamel matrix components for enamel formation. In a ameloblast-associated mouse model mimicking a mutation of the amelogenin gene in amelogenesis imperfect (AI) in protein; humans, the mutated amelogenin forms a complex with ameloblastin, which accumulates in the Apin endoplasmic reticulum/Golgi apparatus and causes ameloblast dysfunction resulting in AI phenotypes. Ameloblastin is a cell adhesion molecule that regulates cell proliferation. It inhibits odontogenic tumor formation and regulates osteoblast differentiation through binding to CD63. Amelotin interacts with Apin/ODAM, but not ameloblastin, while Apin/ODAM binds to amelo- blastin. These interactions may be important for enamel mineralization during amelogenesis. The enamel matrix genes are clustered on human chromosome 4 except for the amelogenin genes located on the sex chromosomes. Genes for these enamel matrix proteins evolved from a common ancestral gene encoding secretory calcium-binding phosphoprotein. # 2014 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction . 48 2. Amelogenin (AMEL) . 49 3. Ameloblastin (AMBN) . 50 * Corresponding author. Tel.: +81 22 717 8380; fax: +81 22 717 8386. E-mail address: [email protected] (S. Fukumoto). 1882-7616/$ — see front matter # 2014 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdsr.2014.01.001 48 S. Fukumoto et al. 4. Enamelin (ENAM) . 51 5. Amelotin (AMTN) and Apin/ODAM . 52 6. Evolution of enamel matrix genes . 52 7. Conclusion . 53 Acknowledgements. 53 References . 53 completely degraded by specific proteases such as MMP- 1. Introduction 20, mainly produced during the secretory/transition stage, Dental enamel, known as the hardest tissue in vertebrates, is and KLK4, mainly produced during the transition/maturation formed by ameloblasts derived from the oral epithelium. In stage, resulting in a highly ordered and purposefully designed the initial stage of the enamel organ’s development, the oral meshwork of carbonated hydroxyapatite crystals with aston- epithelium invades the dental mesenchyme, followed by ishing mechanical properties [1]. differentiation into four types of epithelial cells, including Cell adhesion to the extracellular matrix is of fundamental the inner enamel epithelium, the stratum intermedium, the importance for a wide range of cellular functions, including stellate reticulum, and the outer enamel epithelium. Among cell differentiation, proliferation, and survival [2]. Inner and these cell types, the inner enamel epithelium differentiates outer enamel epithelial cells interact with the basement into enamel matrix-secreting ameloblasts. The formation of membrane, of which major constituents are type IV collagen, dental enamel is a prototype of functional organ develop- laminin, and heparan-sulfate proteoglycan perlecan. For ment through a matrix mineralization process (Fig. 1). Unlike example, laminin a5 (Lama5)-deficient mice show small tooth dentin and bone matrices, in which collagen I is the major germs without a cusp [3]. In addition, proliferation and polar- matrix protein, enamel matrices consist of a distinct set of ization of the dental epithelium are inhibited in these mice, matrix molecules with amelogenin being the major compo- indicating that interactions between the dental epithelium nent. The different matrix components in enamel contribute and the basement membrane are important to determine to its larger and more rigid hydroxyapatite crystal structures tooth sizes and dental epithelial cell differentiation. than dentin and bone. Enamel matrix proteins are produced Ameloblasts are polarized in the secretory stage and at their highest levels by ameloblasts during the secretory secrete enamel matrix components, including amelogenin and transition stages of amelogenesis and collectively (AMEL), ameloblastin (AMBN), and enamelin (ENAM). orchestrate the proper assembly and growth of crystals Furthermore, amelotin (AMTN) and Apin/odontogenic ame- within mineralized enamel. These proteins are nearly loblast-associated (ODAM) are secreted from those in the Figure 1 Oral epithelium differentiates into four types of dental epithelium: inner and outer enamel epithelium, stratum intermedium, and stellate reticulum. Inner enamel epithelium differentiates into pre-ameloblast and ameloblast. Inner enamel epithelium and pre-ameloblast secrete and bind to basement membrane. Secretory-stage ameloblasts secrete enamel matrices AMEL, AMBN, and ENAM. Maturation-stage ameloblasts secrete AMTN and Apin/ODAM. New insights into the functions of enamel matrices 49 Table 1 Summary of enamel matrix. Matrix name Expression Human cytogenetic Mouse KO phenotype Reference (abbreviation) localization Amelogenin (AMEL) Ameloblast (secretory), Xp22.2 (AMELX), Amelogenesis imperfecta [9] odontoblast, osteoblast, Yp11.2 (AMELY) tooth root resorption cementoblast, epithelial reduced bone formation rests of Malassez Ameloblastin (AMBN) Ameloblast (secretory), 4q13.3 Amelogenesis imperfecta [18] odontoblast, osteoblast, reduced bone formation cementoblast, epithelial tumor formation rests of Malassez Enamelin (ENAM) Ameloblast (secretory) 4q13.3 Amelogenesis imperfecta [33] (ENU induced) Amelotin (AMTN) Ameloblast (maturation) 4q13.3 Apin/odontogenic, Ameloblast (maturation) 4q13 ameloblast-associated (ODAM) maturation stage. These enamel matrix components are ancestor of extant mammals, whereas the 3-prime portion considered important for enamel crystal formation. In fact, evolved independently within different mammal species. AMEL and ENAM mutations are identified in patients with The boundary is marked by a transposon insertion in intron amelogenesis imperfecta (AI), a common group of inherited 2, which is shared by all of the examined species [9]. defects of dental enamel formation that exhibit marked Mutations in the AMEL gene in humans and AMEL deficiency genetic and clinical heterogeneity, with at least 14 different in mice cause defective enamel [10] and result in the diverse sub-types recognized on the basis of their clinical appearance group of genetically altered conditions collectively known as AI and mode of inheritance [4—6]. However, a recent study that in humans. AMEL null mice showed remarkable resorption of used a gene-targeting method and in vitro analysis showed cementum and root dentin via the receptor activator of that these matrices also have a large number of biological nuclear factor-kappa B ligand-mediated osteoclastogenesis functions in addition to enamel formation, including bone [11], suggesting that AMEL is negative regulator of osteoclast formation, tumorigenesis, and the regulation of stem cell genesis [12]. In fact, in vivo application of AMEL suppresses function. Mineralized tissue formation and maintenance are root resorption [13]. The enamel layer in AMEL null mice is controlled by matrix proteins such as several secretory cal- hypoplastic and missing a characteristic prism pattern, while it cium-binding phospho-proteins (SCPPs), which are encoded has an elemental composition consistent with a hydroxyapa- by SCPP genes clustered on human chromosome 4 [7]. Half of tite-like mineral [10], suggesting that AMEL is necessary for these proteins, including bone sialoprotein, osteopontin, enamel organization, but not mineral crystal initiation. A dentin sialophosphoprotein, and dentin matrix protein, are tyr64-to-his missense mutation in the tri-tyrosyl domain of associated with bone and dentin formation, while the other the enamel extracellular matrix protein in mice (AMELX) half of consists of enamel-associated proteins, including results in severe defects of enamel biomineralization asso- AMBN, ENAM, AMTN, and Apin/ODAM (Table 1). They promote ciated with an absence of the full-length AMEL protein in the mineral nucleation through calcium ion sequestration and enamel matrix; this mutation also increases ameloblast apop- control crystal growth by adsorption onto growing crystal tosis [14]. In that study, affected ameloblasts express, but fail surfaces [8]. Here, we present the