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In vivo Application of Amelogenin Suppresses Root Resorption
Y. Yagi1,4,
N. Suda1,4,*,
Y. Yamakoshi1,4,
O. Baba3 and
K. Moriyama1,4
1 Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan;
2 Department of Biologic and Materials Sciences, University of Michigan Dental Research Laboratory, Ann Arbor, MI, USA;
3 Biostructural Science, Department of Hard Tissue Engineering, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and
4 Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo, Japan
Correspondence: n-suda. mort{at}tmd.ac.jp
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ABSTRACT
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Amelogenin is recognized as an enamel protein associated with enamel formation. Besides this well-known function, remarkable root resorption has been seen in amelogenin-null mutant mice. Moreover, in vitro culture studies showed that amelogenin suppressed osteoclast differentiation. These studies raised the hypothesis that amelogenin can inhibit root resorption by reducing odontoclast number. To examine this hypothesis, we applied porcine amelogenins in a rat root resorption model, in which maxillary first molars were replanted after being air-dried. Compared with untreated and carrier-treated tooth roots, the application dramatically reduced the odontoclast number on root surfaces and inhibited cementum and root dentin resorption. Amelogenin significantly reduced the number of human odontoclastic cells in culture. It also inhibited RANKL expression in mouse bone marrow cell cultures. All these findings support our hypothesis that amelogenin application suppresses root resorption by inhibiting odontoclast number, and suggest that this is mediated by the regulation of RANKL expression.
Key Words: amelogenin • enamel matrix derivative • odontoclast • root resorption
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INTRODUCTION
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Resorption of the shedding deciduous teeth is a physiological event required for normal development of the permanent dentition (Nanci, 2007). In contrast, root resorption of permanent teeth occurs by various pathological etiologies (Fuss et al., 2003), including infection, trauma, and tumor (Andreasen, 1985), dental treatments such as orthodontic treatment (Brezniak and Wasserstein, 2002), and tooth replantation/transplantation (Andreasen and Hjørting-Hansen, 1966). For tooth longevity, the maintenance of tooth functions, and successful treatment outcome, it is crucial that unfavorable resorption be prevented. As a pharmacological approach, an application of fluoride was examined in animal models, but the expected inhibitory effect was not seen (Foo et al., 2007).
Amelogenin is known as a major constituent of the enamel matrix secreted by ameloblasts and plays an important role in enamel formation (Termine et al., 1980). A previous study demonstrated its expression in periodontal tissues as well (Fong and Hammarström, 2000). Interestingly, significant root resorption was found in amelogenin-gene knockout mice, suggesting this protein as a negative regulator of odontoclastic root resorption (Hatakeyama et al., 2003). Moreover, the application of Emdogain® (Straumann, Basel, Switzerland), which is known to contain amelogenin (Maycock et al., 2002) and is widely used to promote periodontal tissue regeneration (Hammarström et al., 1997), inhibited root resorption in animal (Hamamoto et al., 2002) and human (Barrett et al., 2005) studies. Amelogenin has also been shown to suppress cultured osteoclast formation and the expression of receptor activator of NF- B ligand (RANKL), which is a pivotal factor for bone resorption (Hatakeyama et al., 2006; Nishiguchi et al., 2007). These studies raised the hypothesis that amelogenin treatment can prevent root resorption and reduce odontoclast number, in vivo. In this study, the effect of porcine amelogenin was examined in an experimental root resorption model, and in an odontoclastic cell culture system. Moreover, the amelogenin treatment was also examined on RANKL expression in culture.
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MATERIALS & METHODS
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Animals
Four- and 6-week-old male Sprague-Dawley rats were purchased from Shizuoka Laboratories Animal Center (Shizuoka, Japan). Experimental procedures were approved by the Experimental Animal Committee of Tokyo Medical and Dental University.
In vivo Model of Experimental Root Resorption
Thirty-five 6-week-old male Sprague-Dawley rats were used. Their maxillary right first molars (M1s) were extracted under anesthesia. All extracted teeth were air-dried at room temperature for 1 hr to induce root resorption. Then, the extracted M1s were replanted into the alveolar sockets, and the animals were killed 1 wk later for the following experiments. A 30-µL quantity of Emdogain® was applied to each tooth root at replantation in 7 rats. A 20- or 200-µg quantity of P173, which is an isolated porcine 25-kDa protein lacking exon 4 (Simmer et al., 1994; Yamakoshi et al., 1994), was mixed with 30 µL (3.0 g/L; 150 cP) of propylene glycol alginate (PGA; Wako, Osaka, Japan), which is a carrier of Emdogain®, and applied to each root at replantation (n = 7 for each group). As a control, no treatment was performed on tooth roots in 7 rats (untreated group), or 30 µL of PGA alone was applied to tooth roots in 7 rats (PGA group).
Micro-computed Tomographic (µCT) Analysis of Tooth Roots
µCT images (InspeXio SMX-90CT, Shimadzu, Kyoto, Japan) were taken before and at 1 wk after the tooth replantation. We used VG Studio MAX (Nihon Visual Science Inc., Tokyo, Japan) to visualize morphological differences on root surfaces.
Tissue Preparation and Tartrate-resistant Acid Phosphatase (TRAP) Staining
The right sides of maxillae were fixed by immersion in 4% paraformaldehyde in 0.1 M of phosphate buffer (pH 7.4), decalcified in 4.13% EDTA (pH 7.0), and dehydrated and embedded in Technovit 7100 (Kulzer, Wehrheim, Germany). Then, 3-µm-thick serial sagittal sections of M1s with surrounding tissues were prepared. TRAP staining was performed on sections as described previously (Suda et al., 2001) and counterstained with methylene blue.
Histomorphometric Analysis
The following parameters were used: (1) resorbed dentin area per total root dentin area (%), (2) odontoclast surface per root surface (%), and (3) numbers of odontoclasts on root surfaces. All observations were carried out under a microscope and with the use of an image-measuring system (Finetec Co. Ltd, Tokyo, Japan).
Biolabeling of Rats by Calcein Injection
Two independent protocols were performed for the labeling of rat tooth roots: (1) M1s of 6-week-old rats were extracted and replanted after 1 hr of air-drying. Rats received a single intraperitoneal injection of calcein (15 mg/kg body weight, Wako) just after the replantation. (2) Rats received consecutive intraperitoneal injections of calcein at 4, 5, and 6 wks of age. At 6 hrs after the final injection, M1s were extracted and replanted with 30 µL of PGA , 30 µL of Emdogain®, or 200 µg of P173 mixed with 30 µL of PGA after 1 hr of air-drying.
In both protocols, rats were killed at 1 wk after replantation. The extraction and replantation of M1s were performed only on the right side, and the left side served as an unextracted control. The maxillae were dissected, fixed by immersion in 4% paraformaldehyde, and embedded in polyester resin (Rigolac 2004; Ouken, Tokyo, Japan) without decalcification. Calcein-labeled ground sections were observed under a fluorescent microscope.
Human Odontoclastic Cell Culture
The protocol for the present experiment involving human samples was approved by the Research Ethics Committee of Tokyo Medical and Dental University, and informed consent was obtained from all volunteers. Extracted shedding deciduous teeth were obtained from healthy volunteers, and periodontal/odontoclastic cells were isolated as previously described (Fukushima et al., 2003). Isolated cells were cultured in  -minimum essential medium (-MEM; Wako) with 10% fetal bovine serum (FBS; Japan Bioserum Co., Nagoya, Japan) in 12-well plates (Sumitomo Bakelite Co. Ltd, Tokyo, Japan). In some cultures, 20 µg /mL of P173 or 1.3 µg /mL of P172 (porcine recombinant amelogenin lacking first methionine from P173) was added. All cultures were maintained in a humidified, 5% CO2 atmosphere at 37°C. After culture, cells were fixed with 4% formaldehyde for 10 min, and TRAP staining was performed as previously reported (Udagawa et al., 1990). Cell nuclei were stained by incubation with 4',6-diamidino-phenyindole (DAPI; Sigma, St. Louis, MO, USA). Immunostaining against anti-human vitronectin receptor (CD51/CD61; BD Biosciences, San Jose, CA, USA) was performed as described (Take et al., 2005) with Histofine (Nichirei Corporation, Tokyo, Japan), according to the manufacturer’s instructions.
Statistical Evaluations
We used Student’s t test to examine the differences in the numbers of cultured cells. We used a one-way ANOVA and PLSD test to examine the differences in values of histomorphometric analysis. All statistical analyses were carried out with Statview (Cary, NC, USA). P-values less than 0.05 were considered significant.
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RESULTS
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The Inhibitory Effect of Amelogenin in the Experimental Root Resorption Model
µCT images showed severe root resorption in M1s of untreated (Figs. 1A–1D ) and PGA-treated (Figs. 1E, 1F) M1s at 1 wk after tooth replantation. Resorption was most apparent in the distal surfaces of mesial roots (Fig. 1A). The application of Emdogain® dramatically suppressed the resorption in these areas (Figs. 1G, 1H). Application of 200 µg of P173 also had a considerable suppressive effect on resorption (Figs. 1K, 1L), and a weaker effect was seen at 20 µg (Figs. 1I, 1J).
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Figure 1. µCT images of the 6-week-old rat M1s before and at 1 wk after replantation. (A,C,E,G,I,K) Images before replantation. (B,D,F,H,J,L) Images at 1 wk after replantation. Distal surfaces of mesial roots (boxed area in A) are highlighted in C-L. M1s untreated (A–D), treated with the carrier, PGA (E, F), with Emdogain® (G, H), and with 20 µg (I, J) and 200 µg (K, L) of P173 mixed with PGA. Arrow in D = root resorption. DS, distal surface; MS, mesial surface.
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Histological observations showed significant root resorption in untreated (Fig. 2B) and PGA-treated (Figs. 2A, 2C, 2G) M1s. The most severe resorption of the cementum and root dentin was seen on the distal surfaces of the mesial roots, by µCT (Fig. 2A). Numerous TRAP-positive odontoclasts were present on root surfaces of untreated (Fig. 2B) and PGA-treated (Figs. 2A, 2C, 2G) M1s. The cementum layer was almost totally resorbed from the root surface (Fig. 2G). The application of Emdogain® markedly inhibited cementum/root dentin resorption, and odontoclasts were rarely seen (Figs. 2D, 2H). M1s treated with 200 µg of P173 showed marked suppression of root resorption and reduced numbers of odontoclasts (Figs. 2F, 2I). A 20-µg quantity of P173 also had a moderate inhibitory effect (Fig. 2E). Quantitative analysis showed that dentin resorption was significantly suppressed in groups treated with Emdogain® and P173 compared with the PGA group (Fig. 3A). The odontoclast surfaces (%) (Fig. 3B) and the odontoclast numbers (Fig. 3C) were significantly decreased in groups treated with Emdogain® and 200 µg of P173. A 20-µg quantity of P173 also significantly reduced resorption on odontoclast surfaces (%) (Fig. 3B).
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Figure 2. Histological observations of the inhibitory effects of amelogenin and Emdogain® on root resorption. (A–I) TRAP staining of 6-week-old rat M1s at 1 wk after replantation (left side of each panel represents the distal side). M1s untreated (B), treated with PGA (A,C), with Emdogain® (D), with 20 (E), and with 200 µg (F) of P173 mixed with PGA. Higher magnification of boxed area (mesial root) in A is shown in C. Higher magnifications of boxed areas in C, D, and F are shown in G, H, and I, respectively. Root dentin is denoted by double-ended arrows in G–I. Bars = 250 µm (A–F) and 25 µm (G–I). Arrowhead in G: TRAP-positive multinucleated cell in the periodontal ligament. Arrows in G and I: TRAP-positive multinucleated odontoclasts on the root surface. AB, alveolar bone; CM, cementum; DN, dentin; P, pulp; PDL, periodontal ligament.
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Figure 3. Quantitative analysis of replanted M1s at 1 wk after replantation, without treatment (untreated), treated with PGA, treated with Emdogain® (EMD), and treated with 20 and 200 µg of P173 mixed with PGA. (A) Resorbed dentin per total root dentin surface (%). (B) Odontoclast surface per root surface (%). (C) Odontoclast number. Odontoclasts were identified as TRAP-positive multinucleated cells (containing more than 2 nuclei) attached to the root surfaces. The analysis was performed from the apex to the bifurcation area of each mesial root. The data for each rat are the average value measured in 3 sections which were more than 20 µm apart from each other. Only sections in the middle part of the tooth root were used for the analysis, and those of buccal and lingual ends (within 40 µm of both ends) were excluded. All data are expressed as means ± SD (n = 7). NS: not significant compared with the PGA group. **p < 0.01 and *p < 0.05 compared with the PGA group.
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De novo Cementum Formation after Replantation
The effects of extraction, 1 hr of air-drying, and replantation were examined on de novo cementum formation in rat teeth. First, calcein-labeling was performed in 6-week-old rats just after the extraction and replantation of M1s (Appendix Fig. 1A). One week after the injection, a calcein-labeled root surface was clearly observed on the unextracted teeth (Appendix Fig. 1B), but not on the replanted teeth (Appendix Fig. 1C), denoting that periodontal tissues had not healed enough in 1 wk for the replanted root surface to be labeled.
Next, rats received injections of calcein at 4, 5, and 6 wks of age, and M1s were extracted and replanted with PGA (Appendix Figs. 1E–1G), Emdogain® (Appendix Figs. 1H–1J), or 200 µg of P173 (Appendix Figs. 1K–1M) at 6 hrs after the final injection (Appendix Fig. 1D). Again, root resorption was apparent in the distal surfaces of mesial roots in PGA-treated teeth (Appendix Fig. 1E), and this was suppressed in both Emdogain®- (Appendix Fig. 1H) and P173-treated (Appendix Fig. 1K) teeth. After 3 injections, 3 labeled layers were seen in the apex of each tooth (Appendix Figs. 1F, 1I, 1L), representing the active cementum formation from ages 4 to 5 wks and from ages 5 to 6 wks. Since the root surface could not be labeled due to the insufficient healing of periodontal tissues in 1 wk after the replantation (Appendix Fig. 1C), de novo cementogenesis after replantation was expected to be seen as an unlabeled layer on the outermost calcein-labeled layer of the root surface in the merged images. In contrast to the active cementum formation from ages 4 to 5 wks and from ages 5 to 6 wks, merged images show that de novo cementogenesis was scarcely seen on PGA-treated (Appendix Fig. 1G), Emdogain®-treated (Appendix Fig. 1J), or P173-treated (Appendix Fig. 1M) teeth after replantation.
Effect of Amelogenin in the Human Odontoclastic Cell Culture
Large and small TRAP-positive (TRAP+) odontoclastic cells were seen in the human odontoclastic cell cultures (Fig. 4A). The majority of TRAP+ odontoclastic cells were mononuclear, and large cells were multinucleated (Figs. 4B, 4C). Most TRAP+ mononucleated cells formed clusters in the cultures (Fig. 4A). In these cultures, many cells were immunopositive for the anti-vitronectin receptor (Fig. 4D), as has been reported for cultured human osteoclasts (Matsuzaki et al., 1999). The TRAP+ odontoclastic cells were evaluated for 72 hrs (Fig. 4E). The number was greatest at 24 hrs and decreased toward 72 hrs. The effect of amelogenin was examined at 24 hrs (Fig. 4F). Both P172 and P173 significantly decreased the cell numbers (Fig. 4F).
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Figure 4. The effect of amelogenin on cultured human odontoclastic cells. (A,B) TRAP staining of cultured cells. (C) DAPI staining of the cultured cell shown in B. (D) Immunostaining with anti-human vitronectin receptor antibody ([insert] the primary antibody was replaced with phosphate buffer; arrowheads denote cells which were stained negatively). Bars = 50 µm (A,D), 20 µm (B,C). (E) Numbers of TRAP-positive (TRAP+) odontoclastic cells cultured for 24, 48, and 72 hrs. Data are expressed as means ± SD from triplicate cultures. (F) Numbers of human TRAP+ odontoclastic cells cultured for 24 hrs, with or without 20 µg /mL of P173 or 1.3 µg /mL of porcine recombinant amelogenin (P172). Data are expressed as means ± SD (n = 10). *p < 0.01 from amelogenin-untreated cultures.
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Effect of Amelogenin on RANKL Expression
To examine whether RANK-RANKL signaling was involved in the mechanism, we treated bone marrow cell culture with amelogenin. P173 treatment significantly decreased the numbers of TRAP-positive multinucleated cells and resorption pits, and it also suppressed RANKL expression (Appendix Fig. 2).
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DISCUSSION
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In this study, porcine amelogenin and Emdogain® inhibited odontoclastic root resorption. Previous studies reported that Emdogain® has an inhibitory effect on root resorption (Hamamoto et al., 2002; Barrett et al., 2005). The present observations support these studies and highlight amelogenin as a major bioactive protein fulfilling this effect in Emdogain®.
In experiments in vivo, extraction and replantation of rat M1s were performed. Tooth replantation and transplantation are widely used in mice and rats to evaluate periodontal (Mine et al., 2005) and pulpal (Hasegawa et al., 2007) healing, dental ankylosis (Lustosa-Pereira et al., 2006), and root resorption (Mori et al., 2006). In the present system, numerous resorption lacunae were seen at 1 wk after the replantation in M1s. Root resorption was most apparent in the distal surfaces of the mesial roots. This was probably because the mesial roots are largest and likely to receive the most serious mechanical stress during extraction and replantation.
P172 and P173 reduced the numbers of human cultured odontoclastic cells. These cells express RANK, RANKL, and calcitonin receptor, and exhibit resorbing activity (Fukushima et al., 2003; Takada et al., 2004), as do odontoclasts in tissues (Oshiro et al., 2001; Nanci, 2007). Interestingly, the porcine leucine-rich amelogenin (LRAP) (Gibson et al., 1991) and the mouse full-length amelogenin significantly decreased the cultured osteoclast numbers (Hatakeyama et al., 2006; Nishiguchi et al., 2007). As an underlying mechanism, amelogenin down-regulated the expression of RANKL, but not osteoprotegerin (OPG). Emdogain® treatment has been reported to suppress the expression of RANK and RANKL in rat experimental periodontitis (Fujishiro et al., 2008). If these results are considered together with the down-regulation of RANKL in the bone marrow culture, it is likely that the inhibitory action of amelogenin in this study was due to suppressed RANKL expression.
At 1 wk after replantation, little de novo formation of cementum was seen in PGA-treated, Emdogain®-treated, or P173-treated teeth. These observations strongly suggest that the inhibition of root resorption seen in µCT images of Emdogain®- and P173-treated teeth was not reflected by de novo cementogenesis in the present limited experimental period.
Since P173 is the predominant amelogenin expressed by porcine ameloblasts (Hu et al., 1996, 2002), this isoform lacking exon 4 was used in the experimental root resorption model. Mice (Simmer et al., 1994) and rats (Li et al., 1995) express different amelogenin isoforms containing and lacking exon 4 (called [A+4] and [A-4], respectively). Mouse [A+4] and [A-4] had differential effects on cultured tooth germs, and only the former could induce the polarization of differentiated odontoblasts and ameloblasts with the induction of dentin formation (Tompkins et al., 2005). Furthermore, when implanted in the hind thigh muscle, rat [A+4] was reported to induce an abundant network of capillaries, whereas [A-4] was less effective (Veis et al., 2000). In the pig, P190 including exon 4 has also been reported, but in a much lesser amount in tooth enamel (Yamakoshi et al., 1994). Porcine exon 4 has a unique gene structure and lacks homology with the mouse exon 4 (Hu et al., 2002). It would be interesting to examine the effects of P190 and isoforms of other species in the present experimental model, to clarify the specific protein fragment essential for the inhibition of root resorption.
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ACKNOWLEDGMENTS
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This study was supported by Grants-in-Aid for Scientific Research (16390604, 16659570, and 18390552), a Grant for Supporting Projects for Strategic Research at Nihon University School of Dentistry at Matsudo (Team: Dental morphogenesis) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the Japanese Ministry of Education, Global Center of Excellence (GCOE) Program, ‘International’ Research Center for Molecular Science in Tooth and Bone ‘Diseases.’ The authors thank Dr. J.P. Simmer (Michigan University), Dr. K. Okabe (Fukuoka Dental College), Dr. S. Oida (Tsurumi University), Dr. H. Fukushima (Kyushu Dental College), Dr. M. Saito (Osaka University), and Dr. M. Shiga (Tokyo Medical and Dental University) for valuable advice. Preliminary reports were presented at the 83th General Session & Exhibition of the IADR and the 9th International Conference on Tooth Morphogenesis & Differentiation.
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental.
Received for publication March 28, 2008.
Revision received October 24, 2008.
Accepted for publication October 28, 2008.
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Journal of Dental Research, Vol. 88, No. 2,
176-181 (2009)
DOI: 10.1177/0022034508329451
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ABSTRACT
INTRODUCTION