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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B489-B495 (2000)
© 2000 The Gerontological Society of America

Stimulation of Prostaglandin E2 and Interleukin-1ß Production From Old Rat Periodontal Ligament Cells Subjected to Mechanical Stress

Noriyoshi Shimizua, Masaru Yamaguchia,b, Kagumi Uesuc, Takemi Gosekia and Yoshimitsu Abikob

a Departments of Orthodontics, Nihon University School of Dentistry at Matsudo, Japan
b Departments of Biochemistry, Nihon University School of Dentistry at Matsudo, Japan
c Departments of Mathematics, Nihon University School of Dentistry at Matsudo, Japan

Noriyoshi Shimizu, Department of Orthodontics, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-Ku, Tokyo 101-8310, Japan E-mail: shimizu-n{at}dent.nihon-u.ac.jp.

Jay Roberts, PhD


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Although the severity of periodontal disease is known to be affected by the age of the host, the pathological role of aging in periodontal disease, especially that attributable to trauma from occlusion, has not been well characterized. Prostaglandin (PG)E2 and interleukin (IL)-1ß are key mediators involved in periodontal diseases, potent stimulators of bone resorption, and are produced by human periodontal ligament (PDL) cells in response to mechanical stress. To investigate age-related changes in the biosynthetic capacity of PGE2 and IL-1ß in PDL cells, we examined the effects of in vivo aging with mechanical tension on PGE2 and IL-1ß expression by rat PDL cells. PDL cells obtained from the incisors of 6-week (young) and 60-week (old) rats were cultured on flexible-bottomed culture plates. The cells were deformed by causing a 9% or 18% increase in surface area at 6 cycles per minute for 1 to 5 days. We found an approximately twofold increase in PGE2 and IL-1ß production by old PDL cells subjected to mechanical tension compared with that by young cells, although the constitutive levels were similar in both. The expression of cyclooxygenase (COX)-2 and IL-1ß mRNA (messenger ribonucleic acid) was enhanced by mechanical tension as determined by use of reverse transcription-polymerase chain reaction (RT-PCR), whereas COX-1 and IL-1ß-converting enzyme mRNA remained unchanged. It is possible that the large amount of PGE2 and IL-1ß produced by PDL cells from an aged host in response to mechanical force may be positively related to the acceleration of alveolar bone resorption.

IT is known that prostaglandin (PG)E2 is involved in the pathogenesis of periodontal diseases (1)(2)(3) and bone resorption (4)(5). Interleukin (IL)-1 is also a key mediator involved in a variety of activities in immune and acute-phase inflammatory responses (6), one of which is known to stimulate bone resorption (7)(8). Recently, a high level of IL-1ß was identified in the gingiva (9)(10) and crevicular fluid (11)(12) of periodontitis patients, implicating this potent cytokine in the disease process.

On the other hand, although it has been shown that the severity of periodontal disease is affected by host age, many studies have suggested that the reason for increased disease severity in elderly people is due to the accumulation of a lifetime of bacterial insults rather than a great increase in the rate of disease progression (13)(14)(15)(16)(17)(18).

However, the role of aging in the pathogenesis and aggravation of periodontal disease, especially that attributable to trauma from occlusion, has not been well characterized. It is reported that trauma from occlusion will result in loss of crestal bone height, an increase in width of the periodontal ligament (PDL), and an increase in tooth mobility (19)(20)(21). The PDL is constantly subjected to occlusal force and mitigates mechanical stress such as occlusal force. Therefore, an investigation of the effects of aging on the response of PDL cells subjected to mechanical stress may be important for the disease process to be explained.

The purpose of the present study, therefore, was to determine the effect of in vivo aging on PGE2 and IL-1ß production by rat PDL cells subjected to mechanical tension.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
PDL Cell Preparation and Application of Cyclic-tension Force
A total of 10 male Wistar strain rats were used for this experiment. Five 6-week (young) rats were purchased from Sankyo Laboratory (Tokyo, Japan), and five 60-week (old) rats were obtained by raising 24-week-old purchased rats for 36 weeks at our animal center. The rats were kept in separate cages in a 12-hour light/dark environment at a constant temperature of 23°C and provided with food and water ad libitum.

After cervical dislocation under intraperitoneal anesthesia, a mandible was removed and the lower incisors carefully extracted. Tissue attached to the mid-third of the lingual surface of the root was removed with a surgical scalpel. The coronal and apical portions of the root were not used to avoid contamination with cells from other tissues. The PDL tissue was placed in 35-mm tissue culture dishes and cultured as described previously (22). We obtained five individual cells from young rats (Cells A–E) and five from old rats (Cells F–J).

When the PDL cells grew and reached large enough number for experiments, they (3 x 105 cells/well) were seeded onto flexible-bottomed plates (Flexcell Corp., McKeesport, PA) and cultured for 24 hrs until the cells attached to the bottom of the plates. Cyclic-tension force was applied to the PDL cells according to our previous study (22) with a Flexercell Strain Unit (Flexcell Corp.). The medium was then replaced with the same medium as described above, except that it contained 2% instead of 10% fetal calf serum (FCS). After the cells were cultured for a further 24 hrs, the medium was changed to the same medium again, and then the cells attached to the bottoms of the plates were elongated by 9% or 18% by the Strain Unit at 6 cycles/min (i.e., 5 sec elongation and 5 sec relaxation) for 1 to 5 days, according to the protocol of our previous study (22)(23). All cells were used at the fifth passage.

Assay for PGE2 and IL-1ß Production
The amount of PGE2 and IL-1ß released into the culture medium was measured, in duplicate, by radio immunoassay (RIA) carried out with a commercially available kit utilizing [125I]-PGE2 and [125I]IL-1ß as tracers (Amersham, Arlington Height, IL). The RIA kit was used in accordance with the manufacturer's instructions and safety data manual. The cross-reactivity of the antibody at 50% B/Bo with PG has been determined as PGE2 = 100%; PGE1 = 5%; and 8-iso-PGE2 = 62%. Cross-reactivity with PGD2, PGF2, 6-keto-PGE2, 6-keto-PGF1, TXB2, and arachidonic acid was less than 0.001%. Inter- and intra-assay coefficients of variation for the PGE2 assay in these experiments were 10.0 and 6.8, respectively.

For IL-1, the cross-reactivity of the antibody at 50% B/Bo has been determined as IL-1ß = 100%; IL-1{alpha} = less than 0.02%; and IL-2,3,4,6,TNF{alpha},{gamma} = less than 0.002%. Inter- and intra-assay coefficients of variation for the assay in these experiments were 8.9 and 3.2, respectively.

RNA Preparation and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) Analysis
Total RNA (ribonucleic acid) of young and old cells, both tensed (3 days) and untensed, was isolated by acid guanidinium thiocyanate-phenol-chloroform extraction (24). cDNA synthesis and amplification by RT-PCR were carried out by means of a GeneAmp RNA kit (Perkin-Elmer, Branchburg, NJ). The PCR (polymerase chain reaction) mixture was subjected to amplification by means of a Gene Amp PCR system 9600 (Perkin-Elmer) set at 94°C for 1 minute, 55°C for 2 minutes, and 72°C for 2 minutes, for 21 to 33 cycles. The primers for cyclooxygenase (COX)-1 and 2, which are rate-limiting enzymes of PG synthesis, IL-1ß, IL-1ß-converting enzyme (ICE), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were purchased from Biologica Co. (Nagoya, Japan). The following primer sequences, with the size of the amplified fragment in brackets and references in parentheses, were used: COX-1 [486bp], 5'-GTC ATG AGT CGA AGG AGT CT-3' and 5'-GAC AGT CTT TGG GTA CAG AG-3'(25); COX-2 [333bp], 5'-TTG CCC AGC ACT TCA CTC AT-3' and 5'-CAG ATC AGA AGC GAG GAC CT-3' (26); IL-1ß [522bp], 5'-AAT GCC TCG TGC TGT CTG AC-3' and 5'AGA GAC CTG ACT TGG CAG AG-3' (27); ICE [423bp], 5'-CAC GAC ACC TGT GCG ATC AT-3' and 5'-AGA TCC TGC AGC AGC AAC TT-3' (28); and GAPDH [222bp], 5'-ACC ACA GTC CAT GCC ATC AC-3' and 5'-TCC ACC ACC CTG TTG CTG TA-3' (29). When the PCR products were sequenced for the validity of our PCR primers, each product had the same DNA sequences as reported previously (data not shown). To evaluate the saturated or incomplete reaction of PCR, we amplified five gene fragments simultaneously every 3 cycles from the 21st to 33rd cycle. PCR fragments amplified by different cycles were electrophoresed on 1.5% agarose gel and subsequently stained with ethidium bromide. The differences between the PCR products were quantitated by luminescent values (average gray scale value multiplied by band area). The relative intensitities were measured by an ATTO densitograph image analyzer (ATTO Corp., Tokyo, Japan).

Statistical Method
Values were calculated as the mean ± standard deviation (SD). Data were subjected to two-way or three-way analysis of variance (ANOVA), as indicated in Results. Tukey-Kramer's test was used for analysis of the difference among the various groups tested. Significance levels are indicated in the figure legends. The SAS/STAT statistical package version 6 (SAS Institute Inc., Tokyo, Japan) was used.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The time course of the effects of mechanical tension and aging on PGE2 production by rat PDL cells using Cell A (young rat) and F (old rat) is shown in Fig. 1. The interaction among the three independent factors (age, time, and tension) was significant ( p < .0001) by three-way ANOVA. Both young and old control PDL cells produced a small amount of PGE2 without the application of tension force. One-day application of mechanical tension to the cells did not affect PGE2 production, whereas, 3- and 5-day application of tension to both young and old cells significantly stimulated PGE2 production compared with that in the corresponding controls ( p < .001). When PGE2 production from PDL cells in response to tension was compared between young and old cells, the old cells produced PGE2 at a significantly higher level (twofold) than did the young cells on days 3 and 5 ( p < .001).



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  		Figure 1. Effects of duration and magnitude of mechanical tension and in vivo aging on PGE2 production by rat PDL cells. A: PGE2 production in response to tension was about twofold higher in the cells obtained from the old rat (Cell F) than those from the young rat (Cell A) on days 3 and 5. B: PGE2 production in response to tension was significantly higher in the old cells (Cell F) than in the young cells (Cell A) in both 9% or 18% tension force, but not in the control condition. Values are mean ± SD for 4 cultures. *Significantly different from corresponding control cells ( p < .001). {dagger}Significantly different from corresponding young cells ( p < 0.001).

 
When both young and old cells were subjected to two different magnitudes of tension force (9% or 18%) for 5 days (Fig. 1), the interaction between age and magnitude of tension was significant ( p < .0001) by two-way ANOVA. PGE2 production was significantly higher in old cells than young cells in both 9% or 18% tension force, but not in the control condition. There was no significant difference of PDL cell proliferation among the various groups at specific time periods.

The time course of the effects of mechanical tension and aging on IL-1ß production by rat PDL cells using Cell A (young rat) and F (old rat) is shown in Fig. 2. The interaction among the three independent factors (age, time and tension) was significant ( p < .0001) by three-way ANOVA. Both young and old control PDL cells produced the same amount of IL-1ß. A 3- and 5-day application of the tension to both young and old PDL cells significantly stimulated IL-1ß production compared with that in the controls ( p < .01). However, the old PDL cells produced IL-1ß at a significantly higher level than did the young cells on days 3 (1.5-fold) and 5 (2-fold, p < .01).



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  		Figure 2. Effects of duration and magnitude of mechanical tension and in vivo aging on IL-1ß production by rat PDL cells. A: IL-1ß production in response to tension was much higher (1.5–2-fold) in the cells obtained from the old rat (Cell F) than those from the young rat (Cell A) on days 3 and 5. B: IL-1ß production in response to tension was significantly higher in the old cells (Cell F) than in the young cells (Cell A) in both 9% or 18% tension force, but not in the control condition. Values are mean ± SD for 4 cultures. *Significantly different from corresponding control cells ( p < .01). {dagger}Significantly different from corresponding young cells ( p < .01).

 
When both young and old cells were subjected to 9% or 18% tension force for 5 days (Fig. 2), the interaction between age and magnitude of tension was significant ( p < .0001) by two-way ANOVA. IL-1ß production was significantly higher in old cells than young cells in both 9% or 18% tension force, and the age difference is greatest for the 18%, much less for the 9%, and nonexistent for the control condition.

In order to examine the individual differences of PGE2 or IL-1ß production, PDL cells obtained from 5 young and 5 old rats were subjected to tension force for 5 days (Fig. 3a, Fig. 4a). In each group tested, the young (Cells A–E) and old (Cells F–J) control cells produced a small amount of PGE2 and IL-1ß without the application of tension force. A 5-day application of tension to both young and old markedly stimulated PGE2 and IL-1ß production in all cells compared with that in the controls, with slight individual differences. However, old cells produced a much larger amount of these factors than young cells did in response to tension force. When these results were statistically examined, there was no significant difference in PGE2 and IL-1ß production between young and old control cells (Fig. 3b, Fig. 4b). Tension force significantly stimulated these factors in both young and old, but the stimulation rate was much higher in old cells (PGE2: 26-fold, IL-1ß: 3.7-fold) than that in young cells (PGE2: 16-fold, IL-1ß: 2-fold), and the old cells produced a significantly higher level of these factors than did the young cells (PGE2: 2.2-fold, IL-1ß: 1.8-fold, p < .01).

For further elucidation of the molecular mechanisms of the induction of PGE2 and IL-1ß activities, COX-1, COX-2, IL-1ß, and ICE mRNA expressions in both the young (Cell A) and old PDL cells (Cell F) subjected to mechanical tension were investigated by RT-PCR analysis (Fig. 5a). Because PGE2 and IL-1ß activities were increased by a 3-day application of tension to the cells, gene expression was investigated on day 3.

Each band of the five gene fragments, amplified simultaneously every 3 cycles, constantly increased as the number of cycles increased, suggesting that the PCR reactions would be neither saturated nor incomplete.

The bands for COX-2 mRNA of both the young and old cells were visible on the 27th cycle, with the bands of the tension applied cells being more intense than those for the nonapplied corresponding controls. Furthermore, the band of old tension applied cells was more intense than that of young applied cells in all cycles tested, even though the bands of both the young and old nonapplied cells were similar.

The bands for IL-1ß mRNA of both the young and old cells were also visible on the 27th cycle, and tension force stimulated the intensity of the bands in both the young and old cells. The band of old tension applied cells was more intense than that of young applied cells in all cycles tested, but the bands of both the young and old nonapplied cells were similar. Although COX-1 and ICE mRNA were similarly expressed in both the young and old cells, they were unchanged by application of tension force. The luminescence values of amplified DNA bands in gels measured by an image analyzer are shown in Fig. 5b.


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Using in vivo aged PDL-derived cells from rats, we demonstrated that 3- and 5-day tension applied to both young and old cells significantly stimulated PGE2 and IL-1ß production compared with those in the corresponding controls, and that old PDL cells produced PGE2 and IL-1ß at a significantly higher level than did young cells.

PGE2 is considered to be one of the most important mediators transducing mechanical stimuli to biological signals, and many studies have shown that PGE is involved in the pathogenesis of periodontal diseases (1)(2)(3) and bone resorption (4)(5). IL-1ß is also one of the potent cytokines known to stimulate bone resorption (7)(8), and it has been identified at high levels in the gingiva and crevicular fluid of periodontitis patients (9)(10)(11)(12). IL-1ß also stimulates other bone resorbing factors such as PGE2 (30)(31), IL-6 (32), and proteinases (33)(34)(35). It is reported that trauma from occlusion will result in loss of crestal bone height, an increase in width of the PDL, and an increase in tooth mobility with no loss of clinical attachment (19)(20)(21). Tatakis (36) also reported that IL-1 is an important factor in periodontal tissue breakdown and may contribute to the pathophysiology of occlusal trauma-induced alveolar bone loss. Furthermore, it is reported that the incidence and severity of periodontal disease increases with age, whereas the rate of progression in periodontal disease does not (37). Older persons tend to have more advanced periodontal disease, even though age is not a determinant of periodontal disease when high levels of oral hygiene are maintained (14). Although periodontal disease is closely related to aging, it is affected by many factors; thus, we should not conclude that all events associated with periodontal disease are directly attributed to aging. In the present study, the expression of factors related to periodontal disease were unchanged with age in the absence of stimulation, whereas these factors markedly increased in the old cells as compared to the young cells, in response to exogenous stimuli. These phenomena may be supported by the results of a clinical study reported by Abdellatif and Burt (38) that found that oral hygiene is of greater relative importance than age as a determinant of periodontitis. Therefore, it may be necessary to prevent the exposure of excessive force from traumatic occlusion in the aged in order to maintain healthy periodontal tissue.

We previously reported that conditioned medium from PDL cells, cultured under stretching, caused bone resorption (22) dependent on IL-1ß and PGs. It is therefore most likely that excessive mechanical force applied to the teeth, such as occlusal trauma, may induce a large amount of PGE2 and IL-1ß synthesis in PDL in a magnitude-dependent manner, and they may be involved in alveolar bone resorption resulting in an increase in tooth mobility. These phenomena may be enhanced in aged people.

On the other hand, orthodontic force is considered to be an excessive mechanical stress, such as the force caused by traumatic occlusion, for PDL cells, and the amount of dental root resorption and destruction of alveolar bone wall during orthodontic treatment is higher in adult patients than in young patients (39)(40). Because a large amount of root resorption is caused by the injection of PGE2 around mobile teeth (41), and PGE2 and IL-1ß have bone-resorbing capacity (4)(5)(7)(8), the severity of root resorption and destruction of alveolar bone wall during orthodontic treatment may also be involved in a larger amount of these bone-resorbing factors produced by the PDL cells of an aged host in response to mechanical force.

However, many other inflammatory factors may be altered in the PDL subjected to mechanical force, such as traumatic occlusion, in vivo. It should be considered that the interaction of these factors is implicated in the aggravation of periodontal destruction. In the present study, semiquantitative RT-PCR analysis was used for the study of gene expressions. Our present data showed that COX-2 and IL-1ß mRNA were constitutively expressed in both young and old cells, and they were more enhanced in the old than in the young cells in response to mechanical tension; however, COX-1 and ICE mRNA remained unchanged in both when tension was applied. Although COX is known as an enzyme involved in PG production to convert arachidonic acid to PGG2 and to reduce PGG2 to PGH2 (42) and ICE is known to cleave the IL-1ß precursor to mature IL-1ß (43), the increase in PGE2 and IL-1ß production by tension was not responsible for the augmentation of either COX-1 or ICE mRNA, but rather for that of COX-2 and IL-1ß mRNA.

We recently reported that in vitro cellular aging stimulated IL-1ß production in stretched human periodontal ligament cells (44) using cellular aged PDL cells obtained by sequential subcaltivation on the basis of the idea presented by Hayflick (45) and Hayflick and Moorhead (46). They reported that the number of cell divisions before the onset of senescence is inversely correlated with the age of tissue donors and concluded that cellular aging in vitro reflects aging in vivo.

However, Rubin (47) has proposed that the reduction in the rate of cell proliferation can be exaggerated by subculturing the quiescent cells under suboptimal conditions, and that the limit on replicative life span is an artifact that reflects the failure of diploid cells to adapt to the trauma of dissociation and the radically foreign environment of long-term cell culture. It is, however, a useful artifact that has given much information about cell behavior under stressful conditions. These studies led us to examine whether the study of in vitro cellular aging can help elucidate the aging process in vivo in terms of cellular aging against mechanical stress.

The results in the present experiment—that IL-1ß is produced in higher amounts in response to tension force—are quite similar to those obtained from our previous study of in vitro cellular aging by the increasing population doubling of human PDL cells (44). There was a slight difference in IL-1ß production response caused by higher tension force (18%) in the cells obtained from old rats compared with the in vitro old human PDL cells in the previous study. This difference may be due to the different aging rate of young and old cells between humans and rats. We used the PDL cells obtained from 6-week (young) and 60-week (old) rats in this experiment, and this aging rate (1:10) was much larger than that of the in vitro aged cells of the previous experiment, which was less than 25% of life span in the young and more than 75% of life span in the old (ratio 1:3). In spite of the different aging rates in the two experiments, the tension force responses were similar in both. Although there may not be a linear correlation between the in vivo and in vitro aging process, with respect to the changes of cellular response by aging subjected to mechanical tension, it is likely that in vivo and in vitro aging may induce similar functional changes of the cells in response to mechanical tension.

The use of humans in aging studies is limited by ethical constraints imposed by society, and in very few cases is the surgical collection of healthy human PDL tissue from aged subjects allowed. Moreover, the individual differences of old subjects coming from general and/or local diseases would also limit any studies that could be conducted. Although we used 10 individual cells from five young and five old rats, the responses in each individual cell were similar in each group. Considering the results of individual cell response, it is most likely that the use of young and old cells obtained from rodents of the same strain is a useful experimental model to study cellular aging.




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  		Figure 3. Effects of mechanical tension and in vitro aging on PGE2 production by PDL cells obtained from 5 young (Cells A–E) and 5 old rats (Cells F–J). A: Application of tension for 5 days stimulated PGE2 production in both the young and old cells, but they were about two-fold higher in the old cells compared with those in the young. B: There was no significant difference in PGE2 production between the 5 young and 5 old control cells, but the old cells produced a significantly higher level of PGE2 (2.2-fold) in response to mechanical tension than the young cells. Values are mean ± SD for 5 individual cells from 4 cultures. *Significantly different from corresponding control cells ( p < .001). {dagger}Significantly different from corresponding young cells ( p < .001).

 



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  		Figure 4. Effects of mechanical tension and in vitro aging on IL-1ß production by PDL cells obtained from 5 young (Cells A–E) and 5 old rats (Cells F–J). A: Application of tension for 5 days stimulated IL-1ß production with slight individual differences. IL-1ß production was about 1.5-fold higher in the old cells compared with those in the young. B: There was no significant difference of IL-1ß production between the 5 young and 5 old control cells, but the old cells produced a significantly higher level of IL-1ß (1.8-fold) in response to mechanical tension than the young cells. Values are mean ± SD for 5 individual cells from each 4 cultures. *Significantly different from corresponding control cells ( p < .01). {dagger}Significantly different from corresponding young cells ( p < .01).

 



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  		Figure 5. Ethidium bromide staining pattern of simultaneously amplified PCR products on agarose-gel electrophoresis. A: Total RNA was extracted from the young, old, tension applied (+), and nonapplied (-) PDL cells (Cells A and F), and 2 µg of total RNA was reverse-transcripted; 1/10 of the cDNA obtained was amplified for each mRNA to obtain DNA fragments of the size indicated. B: The luminescent values of the bands in gels showed quantitative differences between the PCR products. Expression of COX-2 and IL-1ß mRNA was higher in the old tension-applied cells than the young tension-applied cells, but that of COX-1 and ICE mRNA remained unchanged.

 

   Acknowledgments
 
This research was supported in part by Grants-in-Aid for Research for Frontier Science, A-1(11307051), from The Ministry of Education, Science, Sports and Culture of Japan, and by a Nihon University General Individual Research Grant.

Received March 31, 1999

Accepted March 1, 2000


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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