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J Dent Res 82(5): 388-392, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Altered pH Regulation During Enamel Development in the Cystic Fibrosis Mouse Incisor

W. Sui, C. Boyd, and J.T. Wright*

Department of Pediatric Dentistry, Brauer Hall CB 7450, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7450, USA;

* corresponding author, tim_wright{at}dentistry.unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Regulation of pH is necessary to the production of an environment conducive to enamel growth and mineralization. We hypothesize that abnormal extracellular pH in the enamel matrix of mice with the cystic fibrosis gene knocked out (CF mice) results in altered enamel mineralization. The enamel matrix pH during amelogenesis was studied in 10 normal and 10 CF mice. Freshly dissected incisors were immersed in pH indicator or glyoxal bis (2-hydro-xyanil) (GBHA). The normal mouse enamel matrix pH was generally higher and modulated differently than did the CF mouse enamel. GBHA staining showed that normal mice had 2 well-demarcated bands in the maturation zone that correlated to the neutral pH zones, while CF mice showed no staining. These results indicate that CFTR plays a role in pH regulation during enamel development and that a reduced pH results in a lack of calcium influx during enamel maturation and hypomineralization of the CF incisor enamel.

KEY WORDS: CFTR • pH • amelogenesis • ameloblast • enamel • mineralization • calcium


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The enamel-producing ameloblast cells originate from ectoderm and perform multiple functions—including matrix secretion, matrix processing, and regulation of ion movement—during enamel development. Enamel formation can be divided into secretory, transition, and maturation stages, based on the unique developmental processes taking place temporally (Robinson et al., 1978). As the ameloblast’s function changes during each of these developmental stages, it changes morphology and function to control the enamel extracellular matrix and its environment, thereby regulating enamel deposition and mineralization.

Cystic fibrosis (CF), the most common autosomal-recessive disease among Caucasians, is characterized by severely altered function of absorbing and secreting epithelia (Boat et al., 1989). The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that is defective in CF. Moreover, CFTR is thought to control the function of other membrane conductance systems (Kunzelmann and Schreiber, 1999). CFTR regulates the carbonic acid buffer system anions to control the cytosolic and extracellular pH in lung, kidney, and intestine (Illek et al., 1998). Carbonic acid buffer anions play an instrumental role in numerous vital processes in animal cells and tissues (Kunzelmann and Schreiber, 1999). It has been proposed that carbonic acid buffering anions serve as the main buffering system in developing enamel (Smith, 1998).

Regulation of pH during enamel mineralization is considered to be essential for normal apatite deposition and crystallite growth. The net pH in developing enamel is neutral during the secretory stage, while maturation-stage enamel matrix alternates between a neutral and an acid pH. In a simple yet convincing study with a universal staining pH indicator, the full thickness of developing enamel matrix was shown to modulate between neutral and acid pH (Sasaki et al., 1991). The acidic and neutral zones modulated in relation to the ruffle-ended and smooth-ended ameloblasts. It is assumed that each ameloblast modulation cycle begins when a group of ameloblasts starts to create the ruffle border and ends after the ameloblasts are smooth-ended (Smith et al., 1987). The net pH in the developing enamel matrix is thus closely related to the function and morphology of ameloblasts (Takagi et al., 1998).

Early in enamel maturation, most of the organic enamel matrix is processed extracellularly into diffusible small molecules and absorbed, leaving considerable fluid-filled space around the individual apatite crystals (Robinson et al., 1979). Subsequent apatite crystal growth involves the massive discharge of protons and the tight regulation of an appropriate physiological pH. Not only must there be physiologic mechanisms in place to neutralize the massive proton release during mineralization, but pH regulation may also play a role in proteinase optimization, and as a trigger for ameloblast modulation from smooth- to ruffle-ended phenotypes (Smith et al., 1996; Smith, 1998).

Although the CF mouse was developed for study of the pathological processes and treatments of CF in humans, it also appears to be a promising model for the investigation of abnormal enamel development. Molecular studies show that the CFTR gene is expressed in developing teeth and other mineralized tissues (Sui et al., 2001; Arquitt et al., 2002). Interestingly, CF mice have markedly hypomineralized incisor enamel (CF enamel mineral per volume mean = 51% vs. normal mouse enamel = 80% mineral per volume) and have retention of enamel matrix protein (Wright et al., 1996a,b). Therefore, we hypothesize that altered pH regulation in the CF mouse results from loss of CFTR function and leads to abnormal enamel mineralization. CF mice were used to investigate the relationship between the net pH of enamel and enamel development.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All animals were managed according to an IACUC-approved protocol. Ten adult C57BL6 mice and 10 CF-knockout mice (Snouwaert et al., 1992) were divided into control and experimental groups, respectively. The mice were all adults ranging in age from 30 to 100 days. The animals were killed by CO2 inhalation. The upper and lower incisors were immediately dissected, and the enamel organ was removed by being gently wiped with gauze moistened with ice-cold distilled water to expose the whole enamel surface. The exposed enamel was air-dried to reveal the opaque zone denoting the transition stage to serve as a developmental marker and landmark. One upper and one lower incisor were immediately immersed in pH indicator solution (Fisher Scientific, Pittsburgh, PA, USA) for 1–2 min. The contralateral incisors were stained with GBHA for 4 min at room temperature in 100 mL of a 75% ethanol solution containing 0.87 g of GBHA (Sigma Chemicals, St. Louis, MO, USA) and 0.35 g NaOH, pH 13 (McKee and Warshawsky, 1989). GBHA is a calcium-chelator dye that stains non-crystal-bound calcium (McKee and Warshawsky, 1989). After being stained, the incisors were rinsed briefly in 75% ethanol and allowed to air-dry at room temperature. The stained incisors were observed under a dissecting light microscope, compared with the standard pH indicator, and photographed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
pH Evaluation
The distance between the apical end of the incisor and the transition zone appeared similar in the CF and wild-type mice, indicating a similar duration of the secretory stage of development in both animal types. The most apical secretory enamel had a pH close to 6.8, staining light green (Fig. 1AGo). There was a gradual decrease in the pH moving toward the transition zone. The transition zone showed the most acidic area of developing enamel, staining nearly orange (pH 5.5).



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  		Figure 1. Mouse incisor pH. (A) Normal incisor stained with pH indicator showing a near-neutral pH during the secretory stage (S), that becomes acidic during the transition stage (T) and modulates between neutral and acidic pH during the maturation stage (M) (2 yellow bands and 2 light green bands [neutral bands designated with *]). (B) CF incisor stained with pH indicator shows a neutral secretory-stage pH and acidic transitional stage, while the maturation-stage zone appeared to be yellow, indicating a sustained lower pH. (C) Higher magnification of the CF incisor maturation-stage enamel showed multiple fine pigmented and unpigmented horizontal strips decorating the surface.

 
The maturation zone of normal teeth began with an acidic pH staining yellow, followed by a diffuse area staining light green. This pattern was then repeated, producing a pH-staining pattern in normal teeth of 2 yellow bands corresponding to pH 6.1–6.5 and 2 light green stripes corresponding to pH 7.0 (Fig. 1AGo). In contrast, the CF teeth were yellow (pH 6.0) through the entire maturation zone, showing no evidence of the pH returning to neutral, as evidenced by green staining (Fig. 1BGo). Higher magnification of the transition and maturation zones revealed closely spaced strips of pigmented and unpigmented enamel, even prior to being stained, that were sometimes accentuated after being stained (Fig. 1CGo).

GBHA Evaluation
GBHA stained the entire secretory zone of the wild-type incisors light red, while the maturation-stage enamel showed two dark red bands interspersed between unstained areas of enamel (Fig. 2AGo). GBHA-stained areas in the normal teeth corresponded exactly to the green-stained (neutral pH) areas, while the lower pH areas (stained yellow) showed no GBHA staining. The GBHA band occurring in the most mature enamel (most incisal) frequently presented as a doublet with two closely stained red bands being resolved. The CF teeth also showed a generalized light red staining of the secretory zone; however, there was no staining in any area of the maturation zone (Fig. 2BGo). Staining with the pH indicator and with GBHA showed the secretory zone to be of similar lengths and the transition zone to be located in the same apical-incisal region in both normal and CF teeth.



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  		Figure 2. Mouse incisor GBHA staining. (A) Normal incisor stained with GBHA showed minimal staining in the secretory stage (S) enamel, no staining in the transition stage (T), and a modulation during the maturation stage (2 red bands designated with arrows). (B) CF incisor stained with GBHA showed similar secretory (S) and transitional (T) stage staining, but showed no visible staining in the maturation-stage enamel (M).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study indicate that hypomineralized enamel on the CF mouse mandibular incisor (Wright et al., 1996a) has a reduced enamel matrix pH during development that likely disrupts the normal crystal growth and protein processing functions necessary for optimal enamel formation. During enamel mineralization, the actively growing enamel hydroxyapatite crystallites release about 8 hydrogen ions for every new unit cell of hydroxyapatite laid down (Simmer and Fincham, 1995). Mineral deposition occurs at neutral or near-neutral pH conditions, with acidic conditions causing a lack of mineral deposition. When the enamel matrix pH reaches a critically low level, there will actually be mineral loss. Additionally, acidic conditions are generally inhibitory to most enamel proteinases and could result in altered amelogenin or other enamel matrix protein processing (Smith et al., 1996). Therefore, removal of the hydrogen ions released by hydroxypatite is a basic requirement for mineralization to proceed. The reduced pH observed in this study during the maturation stage likely alters the normal process of mineral growth during the maturation stage, resulting in the hypomineralization of CF mouse incisor enamel. Previous studies in rats have shown a developmental defect in enamel mineralization that results from altered pH secondary to respiratory acidosis (Whitford and Angmar-Månsson, 1995). It is possible that enamel defects associated with conditions that affect pH (e.g., inflammation from dental abscess, acidosis resulting from hypoxia, or other conditions) could result from enamel hypomineralization secondary to changes during enamel maturation caused by an acidic environment.

Studies of CFTR in other epithelial cells, such as respiratory epithelium, show that it is involved in regulating pH through several mechanisms. CFTR expression in the developing murine incisor has been shown previously (Arquitt et al., 2002), and, based on the present study, we suggest that CFTR could play a similar role in pH regulation during enamel formation. Although a central function of CFTR expression in tissues is the secretion of fluid containing Cl- and HCO3-, CFTR also functions to regulate other membrane conductances (Kunzelmann and Schreiber, 1999). The major mechanism for the transport of HCO3- across the basolateral membrane is via the electrogenic Na+:HCO3- co-transporter (Aronson et al., 1991). Stimulation of the Na+:HCO3- co-transporter by cAMP is due to the generation of a favorable electrical potential that results from membrane depolarization by Cl- secreted through CFTR (Soleimani and Burnham, 2000). Expression of CFTR in the plasma membrane is required for regulation of the Cl-/HCO3- exchanger (Hogan et al., 1997). Mutations in the CFTR gene altered Cl-/HCO3- exchanger activity independent of the CFTR mutation’s effect on Cl- channel activity (Lee et al., 1999). Taken together, these studies indicate that CFTR is critical for the regulation of HCO3- in cells and pH regulation.

Ameloblasts and other epithelial cells may function similarly and use CFTR as a regulator of HCO3- transport and pH (Fig. 3Go). Transepithelial secretion of HCO3- likely involves HCO3- uptake across the basolateral cell membrane and/or production of HCO3- by intercellular carbonic anhydrase activity, and the apical anion channel (Cl-/HCO3- exchanger) (Soleimani and Burnham, 2000). Intracellular cAMP causes activation of CFTR and secretion of Cl- and HCO3-, leading to basolateral and apical membrane depolarization. This depolarization increases the driving force for the Na+:HCO3- co-transporter and, as a result, enhances HCO3- entry into the cell. Intracellular HCO3- also is produced by carbonic anhydrase and is available for transport. Carbonic anhydrase is present in ameloblasts during the maturation stage and likely contributes to available HCO3- (Kakei and Nakahara, 1996; Toyosawa et al., 1996). HCO3- is then secreted out of the cell via apical Cl-/HCO3- exchangers that are stimulated by CFTR, thereby regulating extracellular pH (Fig. 3Go). The results of the present study suggest that CFTR is an essential regulator of HCO3- in the developing mouse incisor and could be active in the continuous release of HCO3- ions into the enamel layer to neutralize the excess hydrogen ions being released during mineralization (Smith, 1998).



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  		Figure 3. pH regulation by ameloblasts. Schematic diagram illustrating the multiple ion regulators potentially functioning in ameloblasts to regulate pH of the enamel matrix. CFTR regulates the electrogenic Na:HCO3- co-transporter and Cl-/HCO3- exchangers to deliver HCO3- into the developing enamel layer.

 
Ameloblasts are a unique cell type that, unlike respiratory epithelia cells, change their morphology and function during their life cycle. For example, ruffle-ended ameloblasts do not allow ions to pass directly across the cell membranes and have tight junctional complexes to adjacent ameloblasts, preventing incursion of ions between the cells (Prostak and Skobe, 1996). Therefore, HCO3- cannot diffuse from the extracellular fluid through the ameloblast layer to the enamel matrix fluid during the ruffle-ended phase. If HCO3- is not available to the enamel matrix via the extracellular route (between ameloblasts), the transcellular transport system offers a possible mechanism by which HCO3- is translated from the extracellular fluid compartment to the enamel matrix. However, the translocation of HCO3- from the extracellular fluid compartment into the enamel layer during enamel formation is not well-understood. Based on our observation of lower enamel pH in the CF mouse, we suggest that the mutated CFTR down-regulates the activation of basolateral Na+:HCO3- co-transporter and decreases the capability of the HCO3- buffer system in developing enamel.

The number of cycles that ameloblasts modulate between RA and SA phenotypes varies between species and is likely related, at least in part, to the size of the tooth being formed. In the normal mouse, we found 2 GBHA bands, whereas the mandibular rat incisor normally has 4bands (Smith et al., 1987). The fine strips observed in both the normal and CFTR teeth likely result from the cyclical nature of enamel formation and are thus analogous to those seen in rat teeth (McKee et al., 1989).

Abnormal pH regulation in the CF mouse incisor and a lack of GBHA staining suggest that the ameloblasts do not modulate through the smooth-ended morphology associated with a more neutral pH and an altered mechanism of calcium infusion to the enamel matrix considered critical for normal enamel maturation (Takano et al., 1983). The CF maturation-stage ameloblasts lose their tall columnar morphology shortly after the secretory stage and take on a more cuboidal morphology during maturation (Wright et al., 1996b). While it has been suggested that reaching a critically low pH could serve as a trigger for the RA to modulate to a leakier SA morphology (Smith, 1998), the CF mouse ameloblasts maintain a low pH and do not modulate to a morphology associated with GBHA staining (i.e., SA).

Mice lacking the CFTR protein have an altered development of their incisor enamel, while the molars appear to have normal enamel formation (Gawenis et al., 2001). Molecular studies with reverse-transcriptase/polymerase chain-reaction show that CFTR is expressed in developing molars (Sui et al., 2001). The difference between the incisors (hypomineralized enamel) and molars (normal enamel) could be related to the speed and continual development in incisors that make these teeth susceptible to abnormal development secondary to a lack of CFTR. The increased rate and continued enamel formation in the mouse incisor are associated with greater and prolonged liberation of protons during enamel mineralization and the need for robust and stringent pH regulation. The loss of CFTR function in the mouse incisor results in a loss of pH regulation, causing increased retention of enamel matrix proteins and a decreased mineralization of the enamel (Wright et al., 1996a,b). This study provides further evidence that CFTR plays an important role in pH regulation during the maturation stage of enamel formation and suggests that it is especially critical in the rapidly and continuously growing mouse incisor.


   ACKNOWLEDGMENTS
 
We thank Dr. Barbara Grubb at the University of North Carolina for generously providing the CF mice for this study, which was supported by NIDCR Grant #1-RO1 DE12879.

Received June 14, 2002; Last revision January 30, 2003; Accepted February 5, 2003


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 ABSTRACT
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 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aronson PS, Soleimani M, Grassl SM (1991). Properties of the renal Na+-HCO3- cotransporter. Semin Nephrol 11:28–36.[ISI][Medline]

Arquitt CK, Boyd C, Wright JT (2002). Cystic fibrosis transmembrane regulator gene (CFTR) is associated with abnormal enamel formation. J Dent Res 81:492–496.[Abstract/Free Full Text]

Boat TF, Welsh MJ, Beaudet AL, editors (1989). Cystic fibrosis. New York: McGraw-Hill.

Gawenis LR, Spencer P, Hillman LS, Harline MC, Morris JS, Clarke LL (2001). Mineral content of calcified tissues in cystic fibrosis mice. Biol Trace Elem Res 83:69–81.[ISI][Medline]

Hogan DL, Crombie DL, Isenberg JI, Svendsen P, Schaffalitzky de Muchadell OB, Ainsworth MA (1997). Acid-stimulated duodenal bicarbonate secretion involves a CFTR-mediated transport pathway in mice. Gastroenterology 113:533–541.[ISI][Medline]

Illek B, Fischer H, Machen TE (1998). Genetic disorders of membrane transport II. Regulation of CFTR by small molecules including HCO3-. Am J Physiol 275:G1221–G1226.

Kakei M, Nakahara H (1996). Aspects of carbonic anhydrase and carbonate content during mineralization of the rat enamel. Biochim Biophys Acta 1289:226–230.[Medline]

Kunzelmann K, Schreiber R (1999). CFTR, a regulator of channels. J Membr Biol 168:1–8.[ISI][Medline]

Lee MG, Wigley WC, Zeng WZ, Noel LE, Marino CR, Thomas PJ, et al. (1999). Regulation of Cl-/HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. J Biol Chem 274:3414–3421.[Abstract/Free Full Text]

McKee MD, Warshawsky H (1989). Banding patterns in rat incisor enamel stained by histochemical complexing methods for calcium. Anat Rec 224:7–13.[Medline]

McKee MD, Nanci A, Smith CE, Warshawsky H (1989). Cyclical aspects of enamel maturation and the role of ruffle-ended and smooth-ended ameloblasts. In: Tooth enamel V. Fearnhead RW, editor. Yokohama: Florence Publishers, pp. 41–45.

Prostak KS, Skobe Z (1996). Anion translocation through the enamel organ. Adv Dent Res 10:238–244.

Robinson C, Fuchs P, Deutsch D, Weatherell JA (1978). Four chemically distinct stages in developing enamel from bovine incisor teeth. Caries Res 12:1–11.[ISI][Medline]

Robinson C, Briggs HD, Atkinson PJ, Weatherell JA (1979). Matrix and mineral changes in developing enamel. J Dent Res 58:871–882.

Sasaki S, Takagi T, Suzuki M (1991). Cyclical changes in pH in bovine developing enamel as sequential bands. Arch Oral Biol 36:227–231.[ISI][Medline]

Simmer JP, Fincham AG (1995). Molecular mechanisms of dental enamel formation. Crit Rev Oral Biol Med 6:84–108.[Abstract]

Smith CE (1998). Cellular and chemical events during enamel maturation. Crit Rev Oral Biol Med 9:128–161.[Abstract/Free Full Text]

Smith CE, McKee MD, Nanci A (1987). Cyclic induction and rapid movement of sequential waves of new smooth-ended ameloblast modulation bands on rat incisors as visualized by polychrome fluorescent labeling and GBHA-staining of maturing enamel. Adv Dent Res 12:162–175.

Smith CE, Issid M, Margolis HC, Moreno EC (1996). Developmental changes in the pH of enamel fluid and its effects on matrix-resident proteinases. Adv Dent Res 10:159–169.

Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, et al. (1992). An animal model for cystic fibrosis made by gene targeting. Science 257:1083–1088.[Abstract/Free Full Text]

Soleimani M, Burnham CE (2000). Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes. Kidney Int 57:371–384.[ISI][Medline]

Sui W, Boyd C, Wright JT (2001). Expression of the CFTR gene in different tissues of mice (abstract). J Dent Res 80(Spec Iss):634.

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