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J Dent Res 83(11):880-885, 2004
© 2004 International and American Associations for Dental Research

RESEARCH REPORTS
Biological

Chondroitin Sulfate in Palatal Wound Healing

X.H. Zou1, W.C. Foong1, T. Cao1, B.H. Bay2, H.W. Ouyang3, and G.W. Yip2,*

1 Faculty of Dentistry, National University of Singapore, Singapore;
2 Department of Anatomy, Faculty of Medicine, National University of Singapore, 4 Medical Drive, Block MD 10, Singapore 117597, Singapore; and
3 Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore;

* corresponding author, georgeyip{at}nus.edu.sg.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chondroitin sulfate is up-regulated in granulation tissue during wound healing. To investigate the role of chondroitin sulfate in the wound-healing process after surgical repair of cleft palate, we isolated and cultured rabbit palatal fibroblasts. Treatment with chondroitin-6-sulfate resulted in a dose-dependent increase in cell adhesion and cell proliferation, whereas the reverse effects were seen after chondroitinase degradation of chondroitin sulfate. The biological actions of chondroitin sulfate appeared to be dependent on the presence and position of sulfate groups. Inhibition of glycosaminoglycan sulfation by chlorate treatment led to reduced cell adhesion and cell proliferation and a slower rate of wound closure in vitro. Furthermore, exposure to chondroitin-4-sulfate resulted in a dose-dependent reduction in cell adhesion. Together, these results show that chondroitin sulfate is involved in palatal wound healing.

KEY WORDS: chondroitin sulfate • chlorate • wound healing • cell adhesion • cell proliferation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Congenital cleft palate is one of the most common birth defects, having an incidence of 1.5 to 2 per 1000 births (Mitchell and Wood, 2000). Timely surgical correction is a mainstay of treatment. Critical events for wound healing after surgical closure of cleft palate are cell proliferation, cell adhesion, and cell migration. However, the molecular regulation of palatal wound healing is not well-understood. Recent studies have implicated fibroblast growth factor-2 (FGF-2) and transforming growth factor-ß1 in palatal wound healing (Yokozeki et al., 1997; Kanda et al., 2003). In addition, interferon-gamma has been shown to modulate collagen production and the formation of scar tissue in post-surgical palatal wound healing (Cornelissen et al., 2000). A common feature among these is the involvement of chondroitin sulfate (CS) proteoglycans (Hakkinen et al., 1996; Milev et al., 1998; Hurt-Camejo et al., 1999). In this study, we investigated the function of CS in cell proliferation, cell adhesion, and cell migration during palatal wound healing.

CS is a glycosaminoglycan, composed of alternating, differently-sulfated residues of ß-D-glucuronate and ß-D-N-acetylgalactosamine residues (Murata and Yokoyama, 1985). It can be found within intracellular organelles, on the cell surface, and in the extracellular matrix (Hook et al., 1984). CS has been implicated in the wound-healing process. Fibroblasts derived from granulation tissue, compared with normal gingival fibroblasts, have highly elevated expression levels of versican, a CS proteoglycan (Hakkinen et al., 1996). CS and other sulfated glycosaminoglycans are found in high concentrations in human wound fluid (Penc et al., 1998). Furthermore, injection of glycyl-histidyl-lysine-Cu2+, an activator of wound healing, into full-thickness rat skin wounds results in accumulation of CS and stimulates wound tissue production (Simeon et al., 2000). Together, these studies suggest that CS may be involved in regulating the wound-healing process.

The aim of this study was to examine the roles of CS in palatal wound healing, with the rabbit as a model organism. We investigated the effects of CS on palatal fibroblast proliferation, adhesion, and migration. We also determined if the position of the sulfate group on CS modulates its biological action.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Isolation and Primary Culture of Rabbit Palatal Fibroblasts
All animal experiments were approved by the Ethics Committee, Faculty of Dentistry, National University of Singapore. Soft palatal mucosa was harvested from adult New Zealand white rabbits, weighing between 2.8 and 3 kg, with the use of a Number 18 blade under sterile conditions. The mucosa was washed thrice with 0.9% sodium chloride solution containing 200 units/mL penicillin and 200 µg/mL streptomycin. After removal of the overlying epithelium, the remaining tissues were cut into small pieces and incubated at 37°C for 2.5 hrs in 0.9% sodium chloride, 0.25% collagenase type I, and 0.2% albumin. The palatal fibroblasts were pelleted by centrifugation at 250 g for 10 min, and washed 3 times with culture medium consisting of Dulbecco’s modified Eagle’s Medium, 10% fetal calf serum, 100 units/mL penicillin, and 100 µg/mL streptomycin. The cells were then re-suspended in culture medium supplemented with chlorate, sulfate, bovine trachea chondroitin-4-sulfate, shark cartilage chondroitin-6-sulfate, or chondroitinase ABC (all from Sigma, St. Louis, MO, USA), and cultured at 37°C in a humidified atmosphere with 5% CO2. The culture medium was changed every 3 days. All in vitro assays were carried out with passage 2 cells derived from at least 3 independent animals. Assessment of cultured cells was performed with the use of an Olympus 1X70 inverted microscope (Olympus, Hamburg, Germany).

Cell Adhesion Assay
The palatal fibroblasts were seeded into 24-well plates at a density of 60,000 cells/well and cultured for 8 hrs. The number of fibroblasts adhering to the culture plate was then determined by the CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay (Promega, Madison, WI, USA). Briefly, the tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) was incubated with cultured cells for 1 hr, during which metabolically active cells converted the MTS reagent to a soluble formazan dye. The amount of absorbance, which is proportional to the number of living cells in culture, was then measured at 490 nm.

Cell Proliferation Assay
Cells were seeded into 24-well plates at a density of 30,000 cells/well and cultured for 7 days. The number of fibroblasts after culture was measured at Day 7 by the CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay as described above.

In vitro Wound Closure Model
Cells were grown in six-well plates until they achieved 90% confluence. Using a 100-µL plastic pipette tip, we scraped 3 horizontal lines across the bottom of each well (‘wounding’). The distance between the wound edges was then determined at 0 and 18 hrs after wounding, as a measure of cell migration (Guo et al., 2003).

Scanning Electron Microscopy
Palatal fibroblasts were cultured on glass slides to 90% confluence, and were then wounded as described above. After culture continued for 18 hrs, the cells were fixed in 3% glutaraldehyde and 2% paraformaldehyde in 0.1 mol/L cacodylate for 30 min, followed by 2% osmium tetroxide. The cells were then dehydrated in increasing concentrations of methanol, transferred to acetone, and dried in a Balzers critical-point dryer with liquefied carbon dioxide as the transition fluid. Cells were coated with 20 nm gold by means of a Balzers sputter-coater and examined with a Philips XL-30 field-emission-gun scanning electron microscope.

Statistical Analysis
Cell proliferation, cell adhesion, and in vitro wound healing were compared among treatment groups by Student’s t test or one-way analysis of variance with Tukey’s post-test or test for linear trend, with the use of GraphPad Prism v4.01 for Windows (GraphPad Software, San Diego, CA, USA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Chondroitin Sulfate Regulates Palatal Fibroblast Adhesion and Proliferation
To determine if CS is involved in regulating palatal fibroblast adhesion, we cultured fibroblasts in the presence of chondroitinase ABC, an enzyme that breaks down CS. Degradation of endogenous CS resulted in a significant reduction in the number of adherent cells (Fig. 1AGo), suggesting that CS is needed for cell adhesion. Furthermore, culture medium supplementation with 1000 ng/mL or less of exogenous chondroitin-6-sulfate led to a dose-dependent increase in cell adhesion (Fig. 1BGo). Post-test for linear trend yielded a coefficient of determination (r2) of 0.9321 (p < 0.0001).



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  		Figure 1. Chondroitin sulfate regulates palatal fibroblast adhesion and proliferation. (A) Degradation of chondroitin sulfate by the addition of 0.1 unit/mL chondroitinase ABC to the culture medium for 8 hrs results in a decrease in the number of adherent cells (Student’s t test; p = 0.0076). (B) Conversely, supplementation of the culture medium with chondroitin-6-sulfate for the same time period leads to a dose-dependent increase in cell adhesion (one-way ANOVA; p < 0.0001). (C) In the cell proliferation assay, statistical comparison by one-way ANOVA shows that palatal fibroblasts cultured in the presence of chondroitin-6-sulfate over a seven-day period show a dose-dependent increase in cell numbers (p < 0.0001). Values represent mean ± SEM of 3 experiments.

 
We also studied the effect of exogenous chondroitin-6-sulfate on cell proliferation, as measured by the number of metabolically active cells after a seven-day culture period (Fig. 1CGo). At a concentration of up to 1000 ng/mL, there was a statistically significant dose-dependent increase in cell numbers (r2 = 0.9840; p < 0.0001), showing that chondroitin-6-sulfate is involved in regulating cell proliferation.

Requirement for Sulfate Group for Biological Activity of Chondroitin Sulfate
Chlorate is an inhibitor of glycosaminoglycan sulfation, and has been used in cell, organ, and whole embryo cultures to inhibit sulfation with no significant effect on glycosaminoglycan or protein synthesis or on cell viability (Conrad, 1998; Yip et al., 2002). It acts by competing with sulfate in synthesis of 3'-phosphoadenosine 5'-phosphosulfate, the sulfate donor for glycosaminoglycan sulfation. We have previously shown that 30 mmol/L chlorate is sufficient to abolish chondroitin sulfation completely (Yip et al., 2002).

To determine if the sulfate group of CS is necessary for the biological activity of the molecule, we studied the effects on cell adhesion and cell proliferation of palatal fibroblasts treated with 30 mmol/L chlorate. Cells exposed to chlorate appeared healthy and had the same spindle-shaped morphology as those in the control group cultured in chlorate-free medium. However, there was a significant reduction in adhesion (Figs. 2AGo, 2BGo) and proliferation (Fig. 2CGo) of chlorate-treated cells. The reduction was due to competitive inhibition of glycosaminoglycan sulfation, and was abolished by the addition of 10 mmol/L exogenous sulfate to culture medium containing chlorate (Fig. 2AGo). Furthermore, supplementation of chlorate-containing culture medium with exogenous chondroitin-6-sulfate resulted in an increase in cell adhesion (Fig. 2BGo) and cell proliferation (Fig. 2CGo), as compared with cells exposed to chlorate alone. Together, these results show that the sulfate group is needed for the biological activity of CS.



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  		Figure 2. The sulfate group is required for biological effects of chondroitin sulfate. Palatal fibroblasts were cultured for 8 hrs in normal culture medium, medium supplemented with 30 mmol/L chlorate, or medium with 30 mmol/L chlorate plus (A) 10 mmol/L sulfate or (B) 100 ng/mL chondroitin-6-sulfate (C6S). The number of adherent cells varied among treatment groups (one-way ANOVA; p < 0.0001), with fewer adherent cells in the chlorate-alone-treated group compared with the control group (Tukey’s test; p < 0.001 in both panels). Fibroblasts treated with chlorate plus exogenous sulfate or chondroitin-6-sulfate showed significantly greater adhesion than those treated with chlorate alone (p < 0.001 in each case). (C) In the cell proliferation assay, continuous chlorate treatment also led to reduced cell numbers after a seven-day culture period (p < 0.001). This reduction was significantly blocked by the addition of 100 ng/mL chondroitin-6-sulfate to the culture medium (p < 0.001). Values represent mean ± SEM of 3 experiments.

 
Effect of Chondroitin Sulfate on Cell Migration and Wound Closure in vitro
To determine the effect of CS on cell migration and wound closure, we used an in vitro wound closure model where ‘wounding’ was achieved by horizontal scraping across the bottoms of wells containing 90% confluent palatal fibroblasts (Guo et al., 2003). We determined the rate of wound closure by measuring the distance between the wound edges 18 hrs after wounding occurred (Fig. 3AGo). Starting with an average wound gap of 489 µm, the distance decreased by 92.7% after 18 hrs (Fig. 3BGo). In contrast, the rate of wound closure was dramatically slower in the chlorate-treated group, with only 39.9% reduction in wound gap distance 18 hrs after wounding occurred. This shows that glycosaminoglycans are involved in cell migration and wound closure. The requirement for CS in this process is further supported by the finding that wound closure in the presence of chlorate and exogenous chondroitin-6-sulfate was significantly more rapid than in samples cultured in the presence of chlorate alone (Fig. 3BGo).




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  		Figure 3. Chondroitin sulfate regulates cell migration and wound closure in vitro. (A) Scanning electron micrograph of palatal fibroblasts cultured for 18 hrs in the presence of 30 mmol/L chlorate, after the making of a linear wound as described in MATERIALS & METHODS. The distance between the wound edges is indicated (*). (B) Statistical comparison of the distance between wound edges 18 hrs after wounding occurred shows a significant difference (one-way ANOVA; p < 0.001) among cells cultured in normal medium, medium supplemented with 30 mmol/L chlorate, or medium with 30 mmol/L chlorate plus 100 ng/mL chondroitin-6-sulfate (C6S). The wound gap in the chlorate-alone-treated group was significantly wider compared with that in the control group (Tukey’s test; p < 0.001) or with the group treated with chlorate plus chondroitin-6-sulfate (p < 0.001). Values represent mean ± SEM of 9 wounds per group.

 
Biological Effect of Sulfate Group Position in Chondroitin Sulfate
To determine if the position of the sulfate group in CS influences its biological action, we examined the effect of treatment with exogenous chondroitin-4-sulfate on cell adhesion and cell proliferation of palatal fibroblasts. As in the chondroitin-6-sulfate experiment (Fig. 1CGo), treatment with chondroitin-4-sulfate resulted in a dose-dependent increase in cell proliferation (Fig. 4BGo). However, unlike chondroitin-6-sulfate, which increased the number of adherent cells (Fig. 1BGo), exposure to a concentration of up to 1000 ng/mL chondroitin-4-sulfate led to a dose-dependent reduction in cell adhesion (Fig. 4AGo; post-test for linear trend; r2 = 0.8282; p = 0.0017). These findings suggest that the sulfate group position in CS specifically determines its biological function.



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  		Figure 4. Biological effects of chondroitin-4-sulfate. (A) Palatal fibroblasts cultured for 8 hrs in medium supplemented with chondroitin-4-sulfate showed a dose-dependent reduction in cell adhesion (one-way ANOVA; p = 0.0049). (B) In the cell proliferation assay, statistical comparison shows that continuous supplementation of the culture medium with chondroitin-4-sulfate led to a dose-dependent increase in cell numbers after a seven-day culture period (p = 0.0074). Values represent mean ± SEM of 3 experiments.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have examined the roles of CS and its sulfate group in palatal fibroblast adhesion, proliferation, and migration. Inhibition of chondroitin sulfation slows the wound-closure process in vitro. Both chondroitin-4-sulfate and chondroitin-6-sulfate are involved in promoting cell proliferation, an activity that is dependent on the presence of the sulfate group. However, the two CS species have antagonistic effects on cell adhesion: Chondroitin-6-sulfate increases but chondroitin-4-sulfate reduces adhesion.

Chondroitin Sulfate and Cell Adhesion
Adhesion of fibroblast cells in granulation tissue is a fundamental process in wound healing (Hehenberger et al., 1998). Integrins are a family of transmembrane heterodimeric proteins that are important in cell-cell and cell-extracellular matrix adhesion (Hynes, 1992). Integrin-mediated cell adhesion results in localization of focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, at focal adhesion points and the tyrosine phosphorylation of FAK (LaFlamme and Auer, 1996; Schaller, 2001). A CS binding site has recently been reported in {alpha}4ß1 integrin (Iida et al., 1998). CS is required for {alpha}4ß1 integrin-mediated cell adhesion, and enhances FAK phosphorylation (Yang et al., 2004). This integrin-mediated cell adhesion is inhibited after degradation of CS (Iida et al., 1992).

Chondroitin Sulfate and Cell Proliferation
The FGF family consists of 22 members and is involved in regulating cell proliferation (Ornitz and Itoh, 2001). Binding of FGFs to their receptors results in dimerization and mutual tyrosine phosphorylation of these receptors, and is potentiated by heparan sulfate, a sulfated glycosaminoglycan (Bernfield et al., 1999). FGF-2 has been shown to stimulate proliferation of gingival fibroblasts in vitro (Fujisawa et al., 2003). Myofibroblasts in full-thickness palatal mucoperiosteal wounds express FGF receptors-1 and -2 (Kanda et al., 2003). Furthermore, topical application of FGF-2 results in faster healing of gingival ulcers in rabbits (Fujisawa et al., 2003). Although the role of other sulfated glycosaminoglycans in FGF signaling has been less extensively investigated relative to heparan sulfate, recent studies suggest that CS and dermatan sulfate are also able to bind to FGF-2 and help mediate FGF-2-induced cell proliferation (Milev et al., 1998; Penc et al., 1998).

Chondroitin Sulfate and Cell Migration
In addition to its role in cell adhesion, discussed above, FAK has been shown to facilitate cell spreading and cell migration by down-regulating RhoA activity (Ren et al., 2000; Arthur and Burridge, 2001; Wakatsuki et al., 2003). RhoA is a member of the Rho family of GTPases. Activation of RhoA results in formation of focal adhesions and stress fibers. Although some degree of RhoA activity is needed for cell adhesion to the substrate, a high RhoA activity level inhibits cell migration (Arthur and Burridge, 2001). Indeed, it has been suggested that melanoma CS proteoglycan enhances cell spreading and migration by activating FAK and inhibiting RhoA activity (Yang et al., 2004).

Specific Requirement for Sulfate Group in Chondroitin Sulfate
In rats, the degree of glycosaminoglycan sulfation changes with age (Weinstein et al., 1992). We have shown that the inhibition of chondroitin sulfation results in reduced cell adhesion and cell proliferation and a slower rate of wound gap closure. This is consistent with the findings in U-937 leukemia cells, where the number of sulfate groups on CS (as measured by the charge density) regulates cell proliferation and differentiation (Volpi et al., 1993). We have further shown that, depending on the position of the sulfate group, CS can either increase or decrease cell adhesion. We suggest that changes in the number and position of the sulfate groups affect binding of growth factors and other signaling molecules to CS. Although the mechanism of this interaction is not well-understood in CS, there is well-established evidence that the sulfate group specifically regulates binding of signaling molecules with heparan sulfate. For example, the biological responses of neural precursor cells to FGF-1 and FGF-2 differ, depending on the sulfation pattern of heparan sulfate (Brickman et al., 1998). Heparan sulfation also affects sonic hedgehog signaling during neural tube closure in the mouse embryo (Yip et al., 2002).

In conclusion, we have shown that CS plays an important role in palatal wound healing by regulating cell adhesion, cell proliferation, and cell migration. However, since chlorate inhibits sulfation of all glycosaminoglycans, we cannot exclude the possibility that heparan sulfate or other sulfated glycosaminoglycans may also be involved. Indeed, exogenous sulfate effectively abolishes the biological effects of chlorate on cell adhesion and proliferation, whereas supplementation by chondroitin-6-sulfate alone statistically improves, but does not fully restore to normal, these cellular processes. A combination of differently-sulfated CS species might lead to better improvement in wound healing compared with that achieved with chondroitin-6-sulfate alone. Studies are currently under way in our laboratory to determine this, as well as the possible involvement of other sulfated glycosaminoglycans in wound healing.


   ACKNOWLEDGMENTS
 
The authors are grateful to Y.G. Chan for expert technical assistance. This project was supported by the Academic Research Fund (Grant R-222-000-005-112) from the National University of Singapore.

Received April 2, 2004; Last revision September 3, 2004; Accepted September 7, 2004


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 DISCUSSION
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Fujisawa K, Miyamoto Y, Nagayama M (2003). Basic fibroblast growth factor and epidermal growth factor reverse impaired ulcer healing of the rabbit oral mucosa. J Oral Pathol Med 32:358–366.[ISI][Medline]

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