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J Dent Res 82(8): 646-651, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Expression of MMP-8 and MMP-13 Genes in the Periodontal Ligament during Tooth Movement in Rats

I. Takahashi*, M. Nishimura, K. Onodera, J.-W. Bae, H. Mitani, M. Okazaki, Y. Sasano1, and H. Mitani

Division of Orthodontics and Dentofacial Orthopedics,
1 Division of Molecular Biology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku Sendai, 980-8575, Japan;

* corresponding author, takahasi{at}mail.cc.tohoku.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Periodontal ligament tissue is remodeled on both the tension and compression sides of moving teeth during orthodontic tooth movement. The present study was designed to clarify the hypothesis that the expression of MMP-8 and MMP-13 mRNA is promoted during the remodeling of periodontal ligament tissue in orthodontic tooth movement. We used the in situ hybridization method and semi-quantitative reverse-transcription/polymerase chain-reaction analysis to elucidate the gene expression of MMP-8 and MMP-13 mRNA. Expression of MMP-8 and MMP-13 mRNA transiently increased on both the compression and tension sides during active tooth movement in vivo. The gene expression of MMP-8 and MMP-13 was induced by tension, while compression indirectly promoted the gene expression of MMP-8 and MMP-13 through soluble factors in vitro. Thus, we concluded that the expression of MMP-8 and MMP-13 is differentially regulated by tension and compression, and plays an important role in the remodeling of the periodontal ligament.

KEY WORDS: remodeling • collagen • collagenase • periodontal ligament


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Orthodontic tooth movement results from a combination of biological reactions to the biomechanical stress generated by orthodontic force in the periodontal ligament (PDL) and alveolar bone. The PDL is comprised mainly of types I and III collagens that connect alveolar bone to tooth roots, giving a dynamic mechanical stability to tooth position (Melcher, 1989). It is made up of a complex network of multi-populational cells, including fibroblasts, endothelial cells, epithelial cells, and macrophages. Each of these cells helps maintain PDL tissues, e.g., by producing fibrillar collagens, supplying blood, and promoting the inflammatory response. While many researchers have attempted to clarify how the alveolar bone is remodeled by the interaction of these cellular systems during the application of force (Rygh, 1989; Igarashi et al., 1998; Domon et al., 1999; Kanzaki et al., 2002), little is known about how the PDL is remodeled during tooth movement.

During orthodontic tooth movement, PDL cells play pivotal roles in recruiting osteoclasts by expressing receptor activator for nuclear factor kappa B ligand (Kanzaki et al., 2002). The cells also participate in the remodeling of PDL tissue itself to adapt to the positional changes of teeth. The remodeling of collagen fibers is performed by phagocytosis by PDL fibroblasts (van der Pauw, 2001) and possibly by secreted proteinases produced by PDL cells (Nakaya et al., 1997; Bolcato-Bellemin et al., 2000; Palmon et al., 2000; Chang et al., 2002). Matrix metalloproteinases (MMPs) (Birkedal-Hansen et al., 1993; Jeffery, 1998) are zinc-ion-dependent proteolytic enzymes produced by a wide variety of cells during developmental processes (Sternlicht and Werb, 2001), inflammatory diseases, degenerative articular diseases (Fernandes et al., 2002), tumor invasion (Egeblad and Werb, 2002; Overall and Lopez-Otin, 2002), and wound healing (Armstrong and Jude, 2002). They are classified into several subgroups, i.e., collagenases (MMP-1, -8, and MMP-13), gelatinases (MMP-2 and -9), stromelysins, membrane-type MMPs, and other subfamilies. Most of the MMPs are produced as pro-enzymes, cleaved at the specific site to become a mature form, and then secreted and activated in the presence of zinc and calcium ions (Jeffery, 1998). MMP-1, -8, and -13, which mainly cleave native collagens (Jeffery, 1998), could be considered as enzymes working in the PDL. Indeed, MMP-8 is expressed in PDL fibroblasts during tooth eruption (Tsubota et al., 2002). Thus, they could be candidates for the proteolytic enzymes that play a crucial role in PDL remodeling during tooth movement.

In the present study, we hypothesized that MMPs are expressed in PDL cells during tooth movement. We used an animal model system to elucidate the changes in gene expression patterns of MMP-8 and MMP-13 by using an in situ hybridization (ISH) method and an in vitro experiment with primary PDL cells derived from rat molars.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental Tooth Movement and ISH
Twenty-nine male six-week-old Sprague-Dawley (S-D) rats were used in the present study. Bilateral first molars were moved buccally as described previously (Igarashi et al., 1998). The experimental procedures have been described in detail previously (Takahashi et al., 1996). For ISH, experimental animals were killed at days 2, 4, 7, and 14 after the beginning of the experimental period, while control animals were killed at days 0, 7, and 14. The control and experimental groups each consisted of at least 3 animals. The housing, care, and all of the experimental protocols in the present study were in accordance with the guidelines established by the Tohoku University Medical Institutional Animal Care and Use Committee.

The experimental procedures of ISH analysis have been described elsewhere (Tsubota et al., 2002). The protocol for ISH was based on previous reports (Ohtani et al., 1992), as modified by Tsubota et al.(2002). Eight-µm-thick horizontal sections were cut for ISH analysis. Digoxygenin-labeled cRNA probes were generated as described previously (Tsubota, 2002).

In vitro Experiments
PDL cells were isolated from the first molar roots of six-week-old S-D rats and were incubated in alpha minimum essential medium ({alpha}MEM) supplemented with 10% fetal bovine serum and antibiotics, as previously described (Kanzaki et al., 2001). Compressive force was applied to the PDL cells for 1, 2, and 3 days at 0.1, 0.2, and 0.3 kPa (Kanzaki et al., 2002). Conditioned medium was retrieved from compressed cultures at days 1 and 3. The conditioned medium was applied to {alpha}MEM at 50% of concentration so that we could observe the effects of cytokines secreted by compressed cells at days 1 and 3 of the culture period. Tension force was applied with a Flexer cell plate (Iwaki Glass Co. Ltd., Tokyo, Japan), which pushed up the bottom of the dish in 0.5-mm (10% stretch) or 0.75-mm (15% stretch) steps once a day for 1 and 3 days.

Total RNAs were isolated from cultures by means of a total RNA isolation kit (Qiagen, Hilden, Germany). They were reverse-transcribed, and cDNA fragments of MMP-8, MMP-13, and GAPDH were amplified by PCR (Tsubota et al., 2002). A semi-quantitative RT-PCR method was used to measure the gene expression of MMP-8 and MMP-13. The PCR products were subjected to electrophoresis, and digital images were obtained and analyzed with the use of NIH image software. The expression levels of MMP-8 and MMP-13 relative to GAPDH were statistically analyzed by Fisher’s test or Scheffé’s test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histological Changes in the PDL during Tooth Movement
PDL tissue consists of fibrillar collagen and multi-populational cells. The fibrillar collagen was oriented radially in the PDL in the rats in all age groups (Figs. 1A–Go1CGo).



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  		Figure 1. Photomicrographs of horizontal sections of maxillary first molars from control and experimental animals (hematoxylin and eosin stain). A, D, G, J, and M: Middle-buccal root of first molars at days 0, 2, 4, 7, and 14 (original magnification, x40; Bar in M = 150 µm). B, E, H, K, and N: Tension side at days 0, 2, 4, 7, and 14 (original magnification, x200; Bar in O = 150 µm). C, F, I, L, and O: Compression side of moving teeth at days 0, 2, 4, 7, and 14 (original magnification, x200). Hyalinized tissues were observed at days 2 and 4, shown in D and F. AB, alveolar bone; CEM, cementum; PDL, periodontal ligament; HY, hyalinized tissue; OC, osteoclast; and BV, blood vessel. n = 3.

 
In the sections of experimental samples, teeth were moved buccally (Figs. 1DGo, 1GGo, 1JGo, and 1MGo), and the collagen fibers were elongated on the tension side (Figs. 1EGo, 1HGo, and 1KGo). The PDL was compressed on the compression side at 2, 4, and 7 days (Figs. 1FGo, 1IGo, and 1LGo), and hyalinized tissue appeared in the compression side (Figs. 1DGo and 1FGo) at day 2. Osteoclasts appeared in both the compression and tension sides and around the hyalinized tissue (Figs. 1HGo, 1IGo, and 1LGo). Bone formation became apparent in the tension side at day 4 (Fig. 1HGo). At day 7, the formation of bone spicules progressed along with the stretched periodontal fibers (Fig. 1KGo). After 14 days, the bone remodeling activities had been completed (Figs. 1MGo to 1OGo).

Gene Expression of Types I and III Collagen (Col1a1 and Col3a1)
Both Col3a1 and Col1a1 were expressed in the cells in all the control PDL tissues (Figs. 2AGo and 2BGo). The hybridization signals for both Col1a1 and Col3a1 appeared to be stronger on the tension side at day 4 than during the other experimental periods (Figs. 2CGo and 2DGo). Expression patterns of both Col1a1 and Col3a1 returned to the same level as the controls thereafter (Figs. 2EGo to 2HGo).



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  		Figure 2. Photomicrographs of ISH images of maxillary first molar roots stained for type I collagen (Col1a1) and type III collagen (Col3a1) are indicated (n = 3). Left lane (A, C, E, and G): type I collagen. Right lane (B, D, F and H): type III collagen. A and B, control; C and D, day 4; E and F, day 7; and G and H, day 14. Original magnification: x100. Bar in H = 150 µm.

 
Gene Expression Patterns of MMP-8 and MMP-13 in vivo
MMP-8 was expressed in the cells lining the cementum and in osteocytes embedded in the alveolar bone, but not in any other cells of the PDL in the control sections (Fig. 3AGo), and MMP-13 was not expressed in the cells in the PDL (Fig. 3FGo). On the tension side, expression of MMP-8 and MMP-13 increased transiently in PDL cells and cells lining the alveolar bone surface at day 4 (Figs. 3CGo and 3HGo). Osteocytes in the alveolar bone expressed MMP-8 at days 4 and 7 on the tension side (Figs. 3CGo and 3DGo). The expression patterns of both of the MMPs returned to normal at day 14 (Figs. 3EGo and 3JGo).



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  		Figure 3. ISH images of MMP-8 (Mmp-8) and MMP-13 (Mmp-13) from control samples (n = 3) and from tension (n = 3) and compression sides (n = 3). A through E and K through O are ISH images of MMP-8, and F through J and P through T are of MMP-13. The two left columns are from controls and from the tension side; the two right columns are from the compression side. Arrowheads indicate the positive signals. Original magnification: x200. Bar in T = 150 µm. K and P indicate the hyalinized tissue in the highly compressed area, and L and Q indicate non-hyalinized tissue. AB, alveolar bone; CEM, cementum; PDL, periodontal ligament; HY, hyalinized tissue; OC, osteoclast; and BV, blood vessel.

 
MMP-8 was transiently expressed in the cells around the hyalinized tissue and fibroblasts on the compression side from days 2 to 7 (Figs. 3KGo to 3NGo). MMP-13 was transiently expressed at days 2 and 4 (Figs. 3PGo and 3SGo), but it was not expressed in the cells embedded in the degenerated hyalinized tissue (Figs. 3KGo and 3SGo). Osteocytes in the compression side strongly expressed MMP-13 at days 2 and 4 (Figs. 3QGo and 3RGo). PDL cells and cells lining the resorbed bone surface expressed MMP-13 at day 4 on the compression side (Fig. 3RGo). The expression of MMP-8 and MMP-13 usually returned to the control level by day 14 (Figs. 3OGo and 3TGo).

Gene Expression of MMP-8 and MMP-13 in vitro
The level of PCR amplification of GAPDH from the cDNA samples was constant among all of the samples reverse-transcribed from standardized amounts of total RNA. A tension force of 15% of stretch significantly (P < 0.05) promoted (two-fold) gene expression of MMP-8 after 3 days of culture, while the expression of MMP-13 did not change statistically (Fig. 4AGo). Compression inhibited the gene expression of both MMP-8 and MMP-13 significantly and dose-dependently in vitro (Fig. 4BGo). At 0.3 kPa, gene expression of both MMP-8 and MMP-13 were completly inhibited by day 3 of the culture period (Fig. 4BGo). Application of 0.2 kPa of compressive force progressively and significantly (P < 0.05) inhibited MMP-8 and MMP-13 expression until day 3 of the culture period (Figs. 4CGo and 4DGo).



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  		Figure 4. Densitometric results from semi-quantitative RT-PCR analysis (mean ± standard deviation). The magnitude-dependent effects of tension (A) and compression (B) on mRNA expression of MMP-8 and MMP-13 are indicated. Open bars, MMP-8; solid bars, MMP-13 (A and B: n = 6). Time course changes in the relative expressions of MMP-8 (C) and MMP-13 (D) are indicated. Open bars, control non-compressed cultures; solid bars, compressed cultures at 0. 2kPa (C and D, n = 4). The effects of conditioned media from cultures compressed or not compressed for 1 and 3 days on the expression of MMP-8 (E) and MMP-13 (F) were measured at 1 and 3 days of culture. Open bars, control, noncompressed media; solid bars, compressed media (E and F, n = 3). CM, conditioned media. **P < 0.01, *P < 0.05.

 
The gene expression of MMP-8 was up-regulated 70% at day 3 with the use of conditioned media obtained from day 1 compressed cultures, but the up-regulation was not significant at day 1, nor did it increase by the application of day 3 media (Fig. 4EGo). On the other hand, gene expression of MMP-13 was up-regulated three-fold at day 3 of the culture period by supplementation with conditioned media from day 3 compressed cultures.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The MMPs and collagens examined in this study were expressed in the control PDL tissue. As reported previously (Becker et al., 1991), proteins of types I and III collagen were localized in PDL tissues, and the present results clearly indicate that the cells in PDL tissue produce those collagens. Only MMP-8 was expressed in the cells at the border between PDL fibrous tissue and cementum in the control when measured by ISH, while PCR analysis revealed the expression of both MMP-8 and MMP13. This difference could be the result of the different sensitivities of ISH and RT-PCR. This coincides with results from our previous study (Tsubota et al., 2002), which showed that MMP-8 could mainly degrade native collagenous matrix under physiologic conditions. Since MMP-8 was expressed mainly in the cells lining the cementum but not in other PDL cells, other types of MMPs could contribute to degradation in other areas of the PDL. Additionally, it is known that the degradation of collagen fiber also occurs through phagocytosis by fibroblasts or fibroclasts (van der Pauw et al., 2001), ending with degeneration by cathepsins or other types of lysozomal enzymes (Domon et al., 1999). While it is unclear which mechanism is functionally relevant, it is apparent that they must both be contributing to physiological PDL remodeling. Taken together, the PDL could be under the remodeling phase of collagenous matrix in physiological conditions.

As shown in the RESULTS, MMP-8 and MMP-13 are transiently expressed in PDL cells on the compression side in vivo. Generally, the expression of MMPs is regulated primarily by inflammatory cytokines, such as prostaglandins (PGs) and interleukins (ILs) (Fini et al., 1998; Nishikawa et al., 2002), and their expression in turn is regulated by mechanical strain (Long et al., 2002). It was also known that PDL cells or periodontal gingival cells express IL-6 and tumor necrosis factors under inflammatory periodontal conditions (Wu et al., 1999; Ramamurthy et al., 2002). On the compression side, some of the PDL cells are killed, forming hyalinized tissue, while the PDL cells that do survive under compression secrete IL-1s and PGE2 (Kanzaki et al., 2002; Long et al., 2002). Whereas direct compression of PDL cells inhibited the expression of MMP-8 and MMP-13, conditioned media from compressed cultures induced their expression in the in vitro experiment. Thus, the transient expression that appeared on the compression side in the animal model experiment could be mediated by soluble factors secreted by compressed PDL cells. MMP-8 and MMP-13 each responded differently to the conditioned media; therefore, it is conceivable that the gene expression of MMP-8 and MMP-13 could be regulated differently through soluble factors. This indirect regulation of PDL tissue remodeling could be similar to that of the regulation of osteoclastogenesis in bone remodeling, as revealed in an earlier study (Kanzaki et al., 2002). PGE2 produced by the PDL cells under compressive force promoted the expression of the receptor activator of nuclear factor kappa, resulting in osteoclastogenesis that remodeled the alveolar bone during tooth movement. Therefore, bone remodeling and PDL fiber remodeling share a similar indirect mechanism that induces their degenerative activity prior to the production of new extracellular matrix.

The expression of both MMP-8 and MMP-13 on the tension side was transiently up-regulated. This up-regulation was predominant in MMP-8 in both the animal model and the in vitro model. Previously, it has been demonstrated that the expression of MMP-1 is up-regulated by the application of mechanical stress (Redlich et al., 2001). On the other hand, this is the first time that MMP-8 and MMP-13 expression in both PDL cells and osteocytes was found to be inducible by the application of tension force. Since this up-regulation in the expression of MMP-8 and MMP-13 occurred at the beginning of and parallel to bone formation on the tension side, MMP-8 and MMP-13 could play important roles not only in the remodeling of PDL but also in the remodeling of alveolar bone during tooth movement.

Additionally, in relation to the transient expression of MMPs, the expression of types I and III collagen was transiently increased on the tension side at day 4. Since the MMP-mediated remodeling of the PDL tissue during tooth movement could require production of collagen fibers, collagen genes might be expressed coordinately. Thus, the moving teeth could establish a new position in the alveolar bone with freshly produced PDL fibers.

In conclusion, the present study indicates that both tension and compression induced the gene expression of MMP-8 and MMP-13. The expression of these genes was differentially regulated by compressive force and tension. Further investigations are needed to verify the mediators and the cell types expressing the mediators.


   ACKNOWLEDGMENTS
 
The authors are grateful to Professor emeritus Dr. Manabu Kagayama for his valuable advice. The authors thank Dr. Mirei Miki-Chiba for her advice. This research has been supported by Grant-in-aid #12671986, from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Received November 11, 2002; Last revision February 13, 2003; Accepted March 21, 2003


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 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
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 DISCUSSION
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