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J Dent Res 83(6): 491-495, 2004
© 2004 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Dental Pulp Fibroblasts Contain Target Cells for Lysophosphatidic Acid

R. Gruber1,*,2, B. Kandler1, C. Jindra1, G. Watzak1,2, and G. Watzek1,2

1 Department of Oral Surgery, Vienna Medical University, Waehringerstraße 25a, A-1090 Vienna, Austria; and
2 Ludwig Boltzmann Institute of Oral Implantology, Vienna, Austria;

* corresponding author, reinhard.gruber{at}akh-wien.ac.at


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lysophosphatidic acid (LPA) is a locally produced bioactive phospholipid which is involved in tissue repair. The objective of this study was to determine whether dental pulp tissue also responds to the phospholipid. Effects of LPA on proliferation, differentiation, and mitogen-activated protein kinase (MAPK) signaling of dental pulp fibroblasts (DPF) were examined in vitro. We report that DPF express LPA receptors LPA1, LPA2, and LPA3 and respond to the ligand with increased mitogenic activity. Involvement of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH2-terminal kinase in LPA signaling could be demonstrated by use of specific inhibitors and detection of the phosphorylation status of the kinases. An increased mitogenic activity paralleled a decreased number of alkaline-phosphatase-positive cells and expression levels of dentin sialophosphoprotein and osteocalcin. Together, these results suggest that dental pulp fibroblasts can respond to LPA, a process that may play a role in pulp tissue repair.

KEY WORDS: lysophosphatidic acid • dental pulp fibroblasts • mitogen-activated protein kinase • proliferation • differentiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dental pulp repair is a highly coordinated process, which is orchestrated by a large number of locally produced factors (Smith and Lesot, 2001; Goldberg and Smith, 2004). Dental pulp fibroblasts (DPF), although a heterogeneous cell population, can serve as an in vitro model to identify molecules which may act as paracrine mediators at sites of pulp repair (Goldberg and Smith, 2004). Using this in vitro model, investigators have found vascular endothelial growth factor (Matsushita et al., 2000), platelet-derived growth factor (Denholm et al., 1998), thrombin (Chang et al., 1999), basic fibroblast growth factor (Shiba et al., 1995), and bone morphogenetic protein (Lianjia et al., 1993) to be mitogenic for DPF and to modulate the expression of odontoblastic differentiation markers such as alkaline phosphatase, dentin sialophosphoprotein, and osteocalcin (Papagerakis et al., 2002). The majority of the factors involved in dental pulp repair have been determined to be proteins. However, the question of whether pulp tissue contains target cells for bioactive lipids has not been investigated.

Lysophosphatidic acid (LPA; 1-acyl-sn-glycerol-3-phosphate) is a membrane-derived phospholipid that exerts its functions in an autocrine-paracrine mode of action (Goetzl and An, 1998; Mills and Moolenaar, 2003). LPA is a pleiotropic molecule, which affects cell proliferation, migration, differentiation, survival, and the production of local factors by the target cells (Goetzl and An, 1998; Mills and Moolenaar, 2003). In particular, LPA has been reported to be mitogenic for various cell types such as osteoblasts (Caverzasio et al., 2000), endothelial cells (Panetti et al., 1997), and smooth-muscle cells (Ediger and Toews, 2001) and to modulate osteogenic differentiation (Dziak et al., 2003). Platelets, which are activated at the sites of injury, are a main source of LPA, suggesting that LPA may play a role in tissue repair (Eichholtz et al., 1993; Pages et al., 2001). Moreover, topical application of LPA can enhance wound healing (Balazs et al., 2001). The effects of LPA are mediated via the G protein-coupled receptors LPA1, LPA2, and LPA3 that activate different intracellular signaling pathways (Kranenburg and Moolenaar, 2001). Extracellular-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK) belong to the family of mitogen-activated protein kinases (Chang and Karin, 2001), which can be activated by LPA (Kranenburg and Moolenaar, 2001; Baudhuin et al., 2002; Sorensen et al., 2003; Xu et al., 2003). Antibodies that recognize their phosphorylation status and the kinase-specific inhibitors U0126, SB203580, and SP600125 are tools to determine whether ERK, p38 MAPK, or JNK, respectively, is involved in LPA signaling.

Here we investigated whether dental pulp tissue contains potential target cells for LPA by measuring proliferation, differentiation, and MAPK signaling in DPF.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Isolation and Cultivation of Dental Pulp Fibroblasts
Third molars were collected from six adults (age 23 to 46 yrs) after informed consent had been obtained according to our institutional standards. Dental pulp connective tissue was separated from the root and digested in 3 mg/mL collagenase type I and 4 mg/mL dispase (Roche, Basel, Switzerland) for at least 3 hrs at 37°C (Gronthos et al., 2002). Released cells were cultured in alpha-modified Eagle’s medium ({alpha}MEM) supplemented with 10% fetal calf serum, antibiotics, and antimycotics (all from Gibco, Grand Island, NY, USA). DPF were kept in a humidified atmosphere at 37°C in 5% CO2. Experiments were performed with cells not exceeding 10 passages.

RT-PCR Analysis
Total RNA was extracted from 1 x 106 DPF with TRIzol reagent (Gibco). Aliquots of 2 µg total RNA were primed by random hexamers and converted into cDNA by means of a kit used according to the instructions of the manufacturer (MBI Fermentas, St. Leon-Rot, Germany). RT-PCR analysis was performed in a Perkin-Elmer GeneAmp PCR System 2400 with primer sets and amplification conditions as recently described (Panther et al., 2002; Papagerakis et al., 2002). PCR products were separated in 1.5% agarose gels and photographed with a digital scanning system (Bio-Rad Laboratories, Hercules, CA, USA).

3[H]-thymidine Incorporation
DPF were seeded at 5 x 104 cells/cm2 in 96-well plates (Packard, Meriden, CT, USA). The following day, DPF were stimulated with 0.1, 0.3, 1, 3, and 10 µM LPA (Sigma, St. Louis, MO, USA) in serum-free medium, i.e., {alpha}MEM supplemented with 2.5 µg/mL insulin-transferrin-selenium (Roche, Mannheim, Germany) and antibiotics. In indicated wells, U0126 (Cell Signaling Technology, Beverly, MA, USA), SB203580 (Alexis Corporation, San Diego, CA, USA), and SP600125 (Calbiochem, San Diego, CA, USA), all at 10 µM, were added to the culture medium. 3[H]-thymidine incorporation was performed as described (Gruber et al., 2003).

Ki-67 Immunohistochemistry
DPF were seeded at 5 x 104 cells/cm2 in 96-well plates. The following day, LPA was added to the cultures with and without U0126, SB203580, and SP600125, all at 10 µM, in serum-free medium. After 24 hrs, cells were fixed and stained for Ki67 as recently described (Gruber et al., 2003). The percentage of Ki67-positive nuclei was determined.

Alkaline Phosphatase Activity
DPF were seeded at 5 x 104 cells/cm2 in 48-well plates. The next day, growth medium was replaced by serum-free medium alone or medium supplemented with LPA at 10 µM, BMP-7 (R&D systems, Minneapolis, MN, USA) at 300 ng/mL, and a combination of both factors. DPF were cultured for another 72 hrs, fixed with 10% formalin, and incubated with a substrate containing 4 mg of naphthol AS-TR phosphate in 0.15 mL of N,N'-dimethylformamide and 12 mg of fast blue BB salt (all from Sigma, St. Louis, MO, USA) in 15 mL of 100 mM Tris-HCl (pH 9.6). Positive cells were counted in two random selected microscopic fields.

Western Blot Analysis
Subconfluent DPF were grown in serum-free medium for 24 hrs followed by stimulation with LPA at 10 µM for 5, 15, 45, and 135 min. Cells underwent lysis with SDS buffer containing phosphatase and proteinase inhibitors. Cell preparations were heated for 5 min at 95°C and centrifuged at 10,000 g for 10 min. Cell extracts were separated by 10% SDS-PAGE and transferred onto nitrocellulose membranes (Amersham Pharmacia Biotech, Buckinghamshire, UK). Membranes were blocked in 5% bovine serum albumin in TBS-T and incubated with a 1:1000 dilution of antibodies against phospho ERK1/2 (clone E-4, St. Cruz Biotechnology, Santa Cruz, CA, USA), ERK1 (clone K-23, St. Cruz), phospho p38 MAPK (clone #9211, Cell Signaling Technologies, Beverly, MA, USA), p38 MAPK (clone C-20, St. Cruz), phospho JNK (clone #9251, Cell Signaling), and JNK antibodies (clone C-17, St. Cruz) overnight at 4°C. The first antibody was detected with the appropriate secondary antibody (Dako, Glostrup, Denmark) according to the ECL method (Amersham).

Statistical Analysis
Statistical analysis was performed with data obtained from six independent preparations of DPF. Single data points represent the mean of quadruplicates from 3[H]-thymidine incorporation assay and of duplicates from the counting of alkaline-phosphatase-positive cells. For Ki-67 staining, statistical analysis was performed with the mean of triplicate cultures from two random selected preparations. All experiments were performed at least twice. Data were statistically analyzed by paired t test, with significance assigned at the P < 0.05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression Pattern of LPA Receptors in DPF
DPF from six donors expressed LPA1, LPA2, and LPA3 receptors as determined by RT-PCR analysis. PCR products appeared at the predicted size, with LPA1 showing the strongest amplification signal. No amplification products were obtained when total cellular RNA was subjected to PCR amplification (Fig. 1Go).



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  		Figure 1. Expression profile of lysophosphatidic acid receptors LPA1, LPA2, and LPA3. LPA receptor expression profile in dental pulp fibroblasts (DPF). RNA was extracted and subjected to RT-PCR analysis. Amplification products were separated on 1.5% agarose gels, stained with ethidium bromide, and photographed. Lanes #1-6 represent amplification products of individual preparations of DPF.

 
LPA-induced Proliferation Requires MAPK Signaling
LPA caused a dose-dependent mitogenic response in DPF of six independent preparations. At the highest investigated concentration of 10 µM LPA, a 7.3 ± 2.3-fold increase of 3[H]thymidine incorporation over unstimulated control cultures was observed. Concentrations lower than 1 µM LPA had no effect in this in vitro assay (P > 0.05; Fig. 2AGo). LPA-induced 3[H]-thymidine incorporation was decreased by inhibitors of ERK, p38 MAPK, and JNK signaling: U0126 decreased the mitogenic activity by 39 ± 6% (P < 0.05), SB203580 by 51 ± 5% (P < 0.01), and SP600125 by 47 ± 12% (P < 0.01) (Fig. 2BGo). Immunohistochemical evaluation of the proliferating cell nuclear antigen Ki67 showed that the relative number of Ki67-positive cells increased from 49 ± 6% in medium controls to 73 ± 7% in cultures treated with LPA at 10 µM (P < 0.05; Fig. 2C,DGo).



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  		Figure 2. Effects of LPA on 3[H]-thymidine incorporation of DPF. (A) Dose-response curve of the indicated concentrations of LPA on 3[H]-thymidine incorporation of DPF. The Fig. shows the mean and standard deviation of results from 6 independent preparations, each performed in quadruplicate. *P < 0.05 and **P < 0.01 vs. unstimulated cells. (B) Effects of inhibitors of MAPK signaling U0126, SB203580, and SP600125 on 3[H]-thymidine incorporation by DPF of 6 individual preparations. Results are shown as mean and standard deviation. *P < 0.05 and **P < 0.01 vs. LPA alone. (C) Staining pattern of the nuclear antigen Ki67 in DPF incubated for 24 hrs with and without LPA at 10 µM. (D) Relative number of Ki67-positive cells in the indicated cultures. Data are means and standard deviation of results from triplicates of one donor. *P < 0.05.

 
LPA Increased Phosphorylation of Different MAPK Signaling Pathways in DPF
Western blot analysis showed that DPF constitutively express unphosphorylated ERK, p38 MAPK, and JNK. Incubation of DPF with LPA at 10 µM increased the phosphorylation status of all MAPKs investigated, with pERK and pJNK remaining elevated during the observation period. Phosphorylation of p38 showed a maximum after 15 min and declined thereafter (Fig. 3Go).



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  		Figure 3. Effects of LPA on MAPK phosphorylation in DPF. Serum-starved DPF were exposed to LPA at a concentration of 10 µM for 5, 15, 45, and 135 min. Cell lysates were separated on a 10% SDS-PAGE and blotted onto a nitrocellulose membrane. Phosphorylated (pERK, pp38 MAPK, and pJNK) and unphosphorylated MAPKs were detected by Western blot analysis.

 
LPA Decreased Expression of Differentiation Markers in DPF
LPA at 10 µM decreased the average number of cells staining positive for alkaline phosphatase by 58.6 ± 33.4% when compared with untreated controls (P < 0.05; Figs. 4AGo, 4BGo, 4CGo). LPA also decreased the number of alkaline-phosphatase-positive cells in the presence of BMP-7 at 300 ng/mL by 37.8 ± 12.5% (P < 0.01; Figs. 4AGo, 4BGo). RT-PCR analysis showed that LPA treatment resulted in lower mRNA levels for dentin sialophosphoprotein and osteocalcin in DPF (Fig. 4DGo).




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  		Figure 4. Effects of LPA on alkaline phosphatase activity and expression of differentiation markers. (A) DPF were stimulated for 72 hrs with bone morphogenetic protein-7 (BMP-7) as indicated under serum-free conditions and stained for alkaline phosphatase activity where positive cells appear blue (AP+). (B) Amount of alkaline phosphatase activity per microscopic field, normalized to unstimulated controls. Data are given as means and standard deviation from results of two random selected preparations, each performed in triplicate. *P < 0.05 vs. unstimulated control; **P < 0.01 between marked groups. (C) Representative picture of a microscopic field that shows alkaline-phosphatase-positive cells given in blue. (D) RT-PCR analysis of mRNA isolated from DPF incubated with LPA for 72 hrs.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
LPA is a locally produced bioactive lipid released from activated platelets during the early stages of wound healing and inflammation. It is therefore reasonable to suggest that LPA can also be released at sites of injured dental pulp tissue, where it may play a role during the subsequent healing process. We have shown here that fibroblasts isolated from dental pulps express LPA receptors, indicating the presence of corresponding target cells in dental pulp tissue. The functional responses of LPA receptors to their ligands have been demonstrated by the increased mitogenic activity. LPA at concentrations mitogenic for DPF are likely to occur at sites of inflammation and wound healing (Eichholtz et al., 1993). It is possible that, also in dental pulp tissue, locally produced LPA can reach levels that are sufficient to cause a cellular response. The proliferative response of cells to LPA requires activation of intracellular signaling pathways such as MAPKs, connecting receptor activation in the cell membrane with gene expression in the nucleus (Chang and Karin, 2001). Binding of LPA to its receptors has been reported to increase MAPK signaling in various cell types, such as smooth-muscle cells, astrocytes, and ovarian cancer cells (Baudhuin et al., 2002; Sorensen et al., 2003; Xu et al., 2003). Our experiments show that all MAPKs investigated—i.e., ERK, p38 MAPK, and JNK—were phosphorylated in response to LPA. Moreover, kinase-specific inhibitors decreased LPA-induced proliferation. Our findings suggest that the three MAPKs are involved in the mitogenic process. These observations are in agreement with those from other reports showing that LPA can induce mitogenic activity via ERK and p38 MAPK signaling (Sorensen et al., 2003; Xu et al., 2003), and JNK as a mediator of cell proliferation (Du et al., 2004).

Our finding that LPA decreased the number of DPF staining positive for alkaline phosphatase activity provides further evidence for the existence of LPA target cells within dental pulp tissue. This effect was even observed in the presence of BMP-7, which is a potent inducer of osteogenic differentiation (Manolagas, 2000). In agreement with these findings, LPA reduced mRNA levels of dentin sialophosphoprotein and osteocalcin, which are characteristically expressed by odontoblast-like cells (Papagerakis et al., 2002). Analysis of the data led us to speculate that LPA can maintain odontoblast-like cells in an undifferentiated state. The mechanism may include the transcellular activation of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR){gamma}2 by LPA (McIntyre et al., 2003). PPAR{gamma}2 is a "master gene" that suppresses osteogenic differentiation of mesenchymal progenitor cells, whereas it is responsible for their differentiation into the adipogenic lineage (Manolagas, 2000). It remains to be determined whether DPF staining positive for alkaline phosphatase activity are derived from stem cells capable of forming ectopic dentin upon transplantation into immunodeficient mice (Gronthos et al., 2002). Moreover, the question of which of the LPA receptors are responsible for the observed effects requires further investigation.

Analysis of our data indicates that LPA is a potent mitogen for DPF under in vitro conditions. The mitogenic activity of LPA requires signaling via ERK, p38 MAPK, and JNK. Moreover, LPA decreased the differentiation of progenitor cells into odontoblast-like cells, also in the presence of BMP-7. From analysis of the data reported here, we suggest that dental pulps contain a proportion of cells that can respond to LPA, a mechanism that may play a role in tissue repair.


   ACKNOWLEDGMENTS
 
The authors thank M. Pensch for skillful technical assistance, and M.B. Fischer for helpful discussion. The authors also thank M. Kunschak for improving the fidelity of English grammar and syntax of the manuscript. This work was supported by the Austrian Nationalbank grant No. 9269.

Received June 4, 2003; Last revision April 6, 2004; Accepted April 19, 2004


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 ABSTRACT
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 RESULTS
 DISCUSSION
 REFERENCES
 
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