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J Dent Res 86(5):463-468, 2007
© 2007 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Mouse Molar Dentin Size/Shape is Dependent on Growth Hormone Status

J.R. Smid1,*, J.E. Rowland2, W.G. Young1, K.T. Coschigano3, J.J. Kopchick3,4, and M.J. Waters5

1 Oral Biology and Pathology, School of Dentistry, and
5 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia;
2 AgResearch Limited, Hamilton, New Zealand; and
3 Department of Biomedical Sciences and
4 Edison Biotechnology Institute, Ohio University, Athens, OH, USA

* corresponding author, j.smid{at}uq.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Growth hormone (GH) status affects dental development, but how GH influences tooth size/shape is unclear. Since GH affects dental epithelial proliferation, we hypothesized that GH influences the tooth crown and root dimensions. Dentin matrix dimensions were measured in longitudinal sections of decalcified first mandibular molars from 3 genetically modified mice: giant (GH-Excess) mice and dwarf (GH-Antagonist and GH-Receptor-Knockout) mice. GH status was found to influence crown width, root length, and dentin thickness. Analysis of these data suggests that GH influences both tooth crown and root development prior to dentinogenesis as well as during appositional growth of dentin. This is concordant with the expression of paracrine GH and GH receptors during tooth bud morphogenesis, and of GH receptors in the enamel organ, dental papilla, and Hertwig’s epithelial root sheath during dentinogenesis. Based on prior studies, these GH morphogenetic actions may be mediated by the induction of both bone morphogenetic protein and insulin-like growth factor-1 expression.

KEY WORDS: dentin dimensions • tooth morphogenesis • growth hormone • GH transgenic mice • GH receptor-knockout mice


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Growth hormone (GH) status clearly influences tooth development: Children suffering pituitary dwarfism or GH insensitivity (Laron syndrome) display hypodontia, microdontia, and delayed tooth eruption (Hamori et al., 1974; Sarnat et al., 1988; Kjellberg et al., 2000). Pituitary hypersecretion of GH leads to gigantism in children and acromegaly in adults. The sizes of the dentitions for both these diseases are within the normal range (Levin, 1965). The mechanisms whereby GH deficiency affects tooth size/shape remain to be elucidated. However, we have previously reported that both GH and GH receptors are present during tooth bud formation at the embryonic cap and bell stages (Zhang et al., 1997), and functional GH receptors have been reported to be present on both odontoblasts and ameloblasts (Young, 1995). Indeed, GH increases cell proliferation of the inner dental epithelium (IDE), dental papilla, and Hertwig’s epithelial root sheath (HERS), prior to the cytodifferentiation of odontoblasts (Young et al., 1992, 1995).

Two GH transgenic mouse lines and a GH receptor knock-out mouse line have been developed as models of human pituitary gigantism, pituitary dwarfism, and GH insensitivity dwarfism (Zhou et al., 1997; Kopchick et al., 1999). We recently reported striking changes in the root cementum for the lower first molar teeth of these 3 GH-modified mouse models (Smid et al., 2004). The current study compares the dimensions of dentin matrix in the same teeth, to determine whether GH status also influences crown and root size/shape.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mouse Genotypes
Three different mouse lines were used in the study: giant mice, with transgenic expression of bovine GH driven by a mouse metallothionein-I promoter, which has excessive GH secretion (Kopchick et al., 1999); dwarf bovine GH transgenic mice over-expressing an antagonist bovine GH transgene in which lysine 119 is substituted for glycine 119 (Chen et al., 1991a,b); and dwarf mice whose GH receptor gene is disrupted so that its expression is knocked out (Zhou et al., 1997).

Bovine GH transgenic mice on a B6/SJL background were crossed with female wild-type (Wt) animals of the same background, to yield giant, bovine GH-expressing mice (GH-Excess genotype), with the transgene acting in a dominant manner. Male dwarf bovine GH-Antagonist mice (C57BL/6J background) were mated with female Wt C57BL/6J mice to produce litters (GH-Antagonist genotype) with the dominant transgene. To produce GH-Receptor-KO mouse litters, 129OLA/BalbC male mice heterozygous (Het) for the GH-Receptor-KO mutation were crossed with Het mutant female 129OLA/BalbC mice. Soon after birth, mouse pups were genotyped by polymerase chain-reaction (PCR) with tail DNA (Chandrashekar et al., 1999). All mice were maintained with the same dietary and lighting regimens and in specific pathogen-free conditions.

Ten littermates of each genotype—being, respectively, Wt and GH-Excess mice, Wt and GH-Antagonist mice, and Wt, Het, and homozygous GH-Receptor-KO mice, with numbers balanced for gender where possible—were killed at 45 days after birth.

All animal experimentation was carried out in accordance with NHMRC (Australia) guidelines and was approved by an institutional animal ethics committee.

Tissue Preparation
Mouse heads were bisected sagittally and fixed in 4.0% paraformaldehyde in phosphate-buffered saline (PBS) for 24 hrs at 4°C. Left mandibular molar tooth blocks were decalcified (by radiography) in cold (4°C) neutral EDTA solution, then processed for embedment in paraffin wax. Five-micrometer serial longitudinal paraffin sections were then cut and stained with hematoxylin and eosin (Smid et al., 2004).

Selection criteria for tooth sections used for morphometric analysis were:

These morphological selection criteria, together with the section thickness, small size, and morphology of teeth, provided an inherent standardization of section plane in different samples. With optimal block-alignment, all data were able to be collected from one section per tissue block. Minor variations in root-crown alignment required that some dentin dimensions be measured in appropriate adjacent sections from the same mouse mandible block.

Morphometric Analysis
Images of selected stained sections and a 2.00-mm scalar, taken under identical magnification, were captured digitally (Coolpix camera and BX60 microscope, Olympus, Tokyo, Japan). Measurements of on-screen images of stained sections were made with the use of a morphometric analysis program (Scion Image, Scion Corporation, Frederick, MD, USA).

Ten dimensions of the left mandibular first molar tooth were measured in each mouse:


Figure 1
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  		Figure 1. Outline of a longitudinal section of a mouse mandibular first molar tooth:

  • crown dentin (a), superior to the axis of cemento-enamel junctions (J, J') and enclosed by the dentino-enamel junction (JEJ') (enamel removed by decalcification) and the dentin-pulp interface (PP').
  • crown pulp (b), inferior to crown dentin (a) and superior to the axis of the cemento-enamel junctions (JJ');
  • apical cellular cementum (c), outline;
  • dorsal root dentin (d), inferior to the cemento-enamel junction axis (JP) and enclosed by the dentino-cemental junction (JA) and the dentin-pulp interface (PA);
  • mesial root dentin (e), inferior to the cemento-enamel junction axis (P'J') and enclosed by the dentino-cemental junction (J'A') and the dentin-pulp interface (P'A'); and
  • root dentin of the furcation (f), outline.

Scale bar = 0.50 mm.

 
The areas of cellular cementum (c, Fig. 1Go) and furcation dentin (f, Fig. 1Go) were not measured in this study.

Sections from tissue blocks from both GH Excess mice and GH Antagonist mice provided 10 replicate datasets of all 10 tooth dimensions measured. However, the GH Receptor KO mice tissue blocks yielded only 6 to 9 replications of tooth dimensions.

The morphometric data were analyzed by one-way ANOVA.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The lower first molar teeth of all 3 mutant mouse lines demonstrated size/shape differences dependent on GH status (Figs. 2Go–4GoGo). Analysis of the linear dimensions of the molar dentin of the GH-Excess mice demonstrated that, although the root lengths were increased (Fig. 2BGo), neither the mesio-distal crown width (Fig. 2AGo) nor the root dentin thickness (Fig. 2BGo) was affected by the bovine GH transgene. The increase in root lengths led to the increases (mesial, 27%; distal, 22%) in cross-sectional areas of root dentin (Fig. 2CGo). Interestingly, not only were the dentino-enamel junctions of the GH-Excess mice significantly shorter than those in the Wt mice (Fig. 2AGo), but also their crown pulp areas were significantly smaller (Wt = 0.18 ± 0.01 mm2; GH-Excess = 0.14 ± 0.02 mm2; mean ± SEM, n = 10, P < 0.01). Total crown area (dentin and pulp), in contrast, was unchanged (Wt = 0.62 ± 0.01 mm2; GH-Excess = 0.62 ± 0.00 mm2; mean ± SEM, n = 10).


Figure 2
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  		Figure 2. Measured dimensions of decalcified longitudinal sections of mouse mandibular first molar teeth of bovine GH transgenic B6/SJL mice, with either the giant mutant (GH-Excess) or the wild-type (Wt) genotype (n = 10). (A) Dentino-enamel junction length and mesio-distal crown width. (B) Mesial and distal dentin root lengths and their corresponding (Mesial Width, Distal Width) thicknesses. (C) Cross-sectional areas of coronal (Crown), (Mesial Root), (Distal Root) dentin and their summation (Sum Total) for individual mouse teeth. All mice were 45 days of age. All dimensions are presented as mean ± SEM. * P < 0.05; ** P < 0.01, *** P < 0.001. One-way ANOVA.

 

Figure 3
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  		Figure 3. Measured dimensions of decalcified longitudinal sections of mouse mandibular first molar teeth of bovine GH-Antagonist transgenic C57BL/6J mice, with either the dwarf mutant (GH-Antagonist) or the wild-type (Wt) genotype (n = 10). (A) Dentino-enamel junction length and mesio-distal crown width. (B) Mesial and distal dentin root lengths and their corresponding (Mesial Width, Distal Width) thicknesses. (C) Cross-sectional areas of coronal (Crown), (Mesial Root), (Distal Root) dentin and their summation (Sum Total) for individual mouse teeth. All mice were 45 days of age. All dimensions are presented as means ± SEM. ***P < 0.001; One-way ANOVA.

 

Figure 4
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  		Figure 4. Measured dimensions of decalcified longitudinal sections of mouse mandibular first molar teeth of GH-receptor-knockout 129OLA/BalbC mice with genotype groups: wild-type (Wt), heterozygous (Het) mice, and dwarf homozygous (GH-Receptor-KO). (A) Dentino-enamel junction length and mesio-distal crown width. (B) Mesial and distal dentin root lengths and their corresponding (Mesial Width, Distal Width) thicknesses. (C) Cross-sectional areas of coronal (Crown), (Mesial Root), (Distal Root) dentin and their summation (Sum Total) for individual mouse teeth. All mice were 45 days of age. All data: Wt, n = 8; Het, n = 9; GH-Receptor-KO, n = 7, except (B) Mesial Length (Wt, n = 8; Het, n = 8; GH-Receptor-KO, n = 7), (C) Mesial Root (Wt, n = 8; Het, n = 8; GH-Receptor-KO, n = 7), and (C) Sum Total (Wt, n = 7; Het, n = 8; GH-Receptor-KO, n = 6). All dimensions are presented as means ± SEM. ***P < 0.001; One-way ANOVA.

 
In marked contrast, the GH-Antagonist mice had significantly (P < 0.001) smaller sizes of most measured dimensions compared with their Wt littermates (Fig. 3Go). Most notable were narrower mesio-distal crown widths (Fig. 3AGo), shorter roots, thinner layers of appositional dentin (Fig. 3BGo), and smaller total crown areas (Wt = 0.62 ± 0.02 mm2; GH-Antagonist = 0.51 ± 0.02 mm2; mean ± SEM, n = 10, P < 0.001). GH-Antagonist mice also had smaller areas of crown dentin (approximately 20% smaller, Fig. 3CGo), root dentin (Mesial Root, Distal Root, both approximately 25% smaller; Fig. 3CGo), and "Sum Total" dentin (approximately 25% smaller; Fig. 3CGo) compared with their Wt littermates.

Similarly, the GH-Receptor-KO mice had significantly (P < 0.001) smaller sizes of most measured dimensions compared with their Wt littermates (Fig. 4Go). These included narrower mesio-distal crown widths (Fig. 4AGo), shorter roots (Mesial Length, Distal Length; Fig. 4BGo), thinner layers of appositional dentin (especially Distal Width; Fig. 4BGo), and smaller total crown areas (Wt = 0.68 ± 0.01 mm2, n = 8; GH- Receptor-KO = 0.52 ± 0.04 mm2, n = 7; mean ± SEM, P < 0.001). Moreover, in the absence of a functioning GH receptor, the "Sum Total" area of measured dentin in GH-Receptor-KO mice was about 30% smaller than the size of their Wt littermates (Fig. 4CGo). This area included both the crown dentin area (almost 28% smaller), as well as both mesial and distal root dentin areas (each approximately 38% smaller; Fig. 4CGo).

When each group of data for the 3 mutant mouse lines (Figs. 2Go–4GoGo) was analyzed (by ANOVA) for the effect of gender on dentin dimensions, no significant difference was generally observed.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The use of the GH transgenic (GH-Excess) giant and (GH-Antagonist) dwarf mice together with GH-receptor-KO dwarf mice has shown that GH status affects the dimensions of dentin crowns and roots in molar tooth development. However, not all tooth dimensions were proportionally changed with extremes of GH status; consequently, not only size but also shape of the molar dentin were affected.

Common sense suggests that giant GH-Excess mice would have bigger teeth. This was not the case: The first lower molars of GH-Excess mice had longer roots, but their total crown area and mesio-distal width at the cemento-enamel junction axis were unchanged. This echoed the effects of GH-Excess on tooth dimensions observed in human studies (Levin, 1965). In contrast, with GH-deficiency, the crown dimensions were clearly affected: In both dwarf models (GH-Antagonist mice, GH-Receptor-KO), the total crown area and mesio-distal width at the cemento-enamel junction axis were significantly smaller than in the Wt mice. Deficiencies of GH action can therefore affect mouse molar crown development.

Development of the first mandibular molar tooth is initiated in utero within 2 wks following conception in the mouse (Peterka et al., 2002). The tooth germ undergoes morphogenetic sequential development through bud, cap, and bell stages during embryonic days (ED) 13.5 to 18, and dentinogenesis begins during ED 18 (just prior to birth) (Peterka et al., 2002; Lisi et al., 2003; Gaete et al., 2004). Although the anterior pituitary begins to express GH after only about ED 16 in the mouse (Slabaugh et al., 1982; Seuntjens et al., 2002), GH and its receptor are present in embryonic dental tissues, and GH could act as a paracrine agent during the earlier stages (Zhang et al., 1997). Sizes and shapes of tooth crowns are morphogenetically pre-determined during embryogenesis, through the activities of transitory ectodermal signaling centers, the enamel knots (Thesleff et al., 2001). Enamel knots express the growth factors bone morphogenetic protein 4 (BMP-4), fibroblast growth factor 4 (FGF-4), and sonic hedgehog (Shh). These factors regulate proliferation of cells in the inner dental epithelium and the underlying dental papilla prior to the onset of dentinogenesis. The pattern of cell differentiation determines the shape of the crown dentin (Lisi et al., 2003). GH increases cell proliferation of both the inner dental epithelium and the dental papilla prior to the cytodifferentiation of odontoblasts (Young et al., 1992, 1995). Moreover, GH also up-regulates BMP-4 in both odontoblasts and cementoblasts (Li et al., 2001; Young et al., 2001). Inhibition of BMP-4 expression results in loss of tooth crown morphology (Tabata et al., 2002). Since the actions of GH are deficient in dwarf mouse models, crown dimensions could be affected epigenetically.

The Hertwig’s Epithelial Root Sheath (HERS) determines the dimensions of the roots by proliferation at the epithelial diaphragm and by induction of odontoblasts from the adjacent dental papilla cells. Longer dentin roots and larger dentin root areas in giant mice suggest that excessive GH action stimulates greater mitotic activity in the HERS, thus increasing its extension and increasing the induction of odontoblast differentiation in the dental papilla. Similarly, the shorter dentin roots and smaller dentin root areas in both dwarf mice suggest deficiences in GH action and diminished mitotic activity in the HERS. The GH-receptor is detectable in HERS cells adjacent to the future dentin prior to the differentiation of the odontoblasts (Zhang et al., 1992). Hypophysectomy stops molar root dentin growth in rats, but GH replacement fails to restart this root growth (Clayden et al., 1994); whereas, mitotic activity in the HERS of the continuously growing incisor of the Lewis dwarf rat is stimulated by GH replacement (Young et al., 1992).

Crown dentin apposition was increased in the giant GH-Excess mice (apparent as a reduction in crown pulp area); however, root dentin apposition was unchanged (as indicated by the widths of mesial and distal roots at the cemento-enamel junction axis). Significant reductions in root dentin apposition were observed for the widths of roots in both dwarf (GH-Antagonist, GH-Receptor-KO) mice. In particular, the growth of root dentin of these dwarf mice (38% smaller areas in GH-Receptor-KO mice; 25% smaller areas in GH-Antagonist mice) correlated with their body weight growth (40–65% smaller for GH-Receptor-KO mice; 30–40% smaller for GH-Antagonist genotype) (Zhou et al., 1997; Kopchick et al., 1999; Smid et al., 2004). These latter observations are consistent with the reduced dentin appositional growth observed in Lewis dwarf rats (Young, 1995). In this GH-deficient rat model, GH replacement up-regulates the expression by odontoblasts of some predentin matrix proteins (Young et al., 2001) and their glycan components (Zhang et al., 1994).

While there are many studies of bone growth and metabolism in mouse models that express a GH transgene (Turner et al., 2001; Eckstein et al., 2002) or lack the expression of a GH receptor gene (Lupu et al., 2001; Wang et al., 2004), this is the first morphometric study of dentin in these mouse models. The increase in dentin area in giant GH Excess mice, predominantly in the roots (mesial, 27%; distal, 22%), is comparable with their femoral cortical bone enlargement (males, 35%; females, 32%) (Eckstein et al., 2002). These changes, however, are modest compared with the approximately 80% larger areas of root cellular cementum in the same group of mice (Smid et al., 2004). Similarly, the respective 25% and 30% smaller dentin "sum total" areas of dwarf (GH-Antagonist and GH-Receptor-KO) mice (Figs. 3CGo, 4CGo) are comparable with the 18–65% smaller weights of their visceral organs (Knapp et al., 1994; Zhou et al., 1997). These, again, are modest compared with the respective (approximately 60% and > 90%) smaller areas of root cellular cementum (Smid et al., 2004).

In conclusion, analysis of data from this study suggests that GH influences dentin size/shape not only during dentin appositional growth but also during crown and root morphogenesis prior to dentinogenesis.


   ACKNOWLEDGMENTS
 
We thank Terry Daley (Oral Biology and Pathology, School of Dentistry, University of Queensland) for his histotechnology skills. This work was supported by a NHMRC Grant to MJW, and by an Australian Dental Research Foundation grant to WGY and JRS. JJK is supported by NIH grant #AG19899 and by the State of Ohio’s Eminent Scholars’ Program.

Received December 7, 2005; Last revision November 27, 2006; Accepted December 19, 2006


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chandrashekar V, Bartke A, Coschigano KT, Kopchick JJ (1999). Pituitary and testicular function in growth hormone receptor gene knockout mice. Endocrinology 140:1082–1088.[Abstract/Free Full Text]

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