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J Dent Res 82(9): 687-691, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biomaterials & Bioengineering

Effects of Matrix Metalloproteinase Inhibitors on Bone Resorption and Orthodontic Tooth Movement

L.S. Holliday, A. Vakani, L. Archer, and C. Dolce*

Department of Orthodontics, College of Dentistry, University of Florida, Box 100444, JHMHC, Gainesville, FL 32610-0444;

* corresponding author, cdolce{at}dental.ufl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Matrix metalloproteinases are involved in the regulation of bone remodeling. The hypothesis that matrix metalloproteinase inhibitors may be useful for experimentally limiting orthodontic tooth movement, a process involving perturbations of normal bone remodeling, was tested. General matrix metalloproteinase inhibitors limited the resorption of bone slices by mouse marrow cultures stimulated by calcitriol, parathyroid hormone, and basic-fibroblast growth factor. Pre-coating dentin slices with short arginine-glycine aspartic acid (RGD) peptides, but not arginine-glycine-glutamic acid (RGE) controls, restored bone resorption in the presence of matrix metalloproteinase inhibitors. Orthodontic tooth movement was inhibited by local delivery of Ilomastat, a general matrix metalloproteinase inhibitor, with the use of ethylene-vinyl-acetate (ELVAX) 40, a non-biodegradable, non-inflammatory sustained-release polymer. This study shows that orthodontic tooth movement can be inhibited with the use of matrix metalloproteinase inhibitors, and suggests a mechanistic link between matrix metalloproteinase activity and the production of RGD peptides.

KEY WORDS: matrix metalloproteinase inhibitors • bone resorption • orthodontic tooth movement


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Normal bone remodeling involves an intricately linked set of processes (Rodan, 1998). Resorption of bone by osteoclasts is coupled with subsequent bone formation by osteoblasts. Local and systemic factors—including cytokines, hormones, growth factors, and mechanical stimulation—activate osteoblasts to produce osteoprotegerin-ligand, which is vital for osteoclast differentiation and activity (Lacey et al., 1998). Osteoblasts also regulate mature osteoclasts downstream of osteoprotegerin-ligand in other ways, including through interstitial collagenase activity (Holliday et al., 1997, 2003).

When a force is applied to a tooth, structural and biochemical changes occur in the periodontal ligament (PDL) space so that remodeling in the surrounding tissues can take place (King et al., 1991; Rody et al., 2001). Force application disrupts the equilibrium that exists between bone formation and resorption, resulting in more bone resorption than formation on the pressure side and more bone formation than resorption on the tension side.

During bone remodeling, components of the extracellular matrix, such as collagen, are degraded and removed, and new components are synthesized and deposited. Recent work has established that members of the family of matrix metalloproteinases (MMPs) are key enzymes in matrix degradation (Delaisse et al., 2000). MMPs are a family of zinc-dependent endopeptidases comprised of over 25 enzymes regulating many biological processes, including development, morphogenesis, and wound healing (Woessner, 1991). Recent studies indicate that the activity of MMPs is important for activating osteoclasts to resorb bone. Interstitial collagenase cleavage of type I collagen has been implicated in triggering bone resorption in vitro and in vivo (Holliday et al., 1997, 2003; Zhao et al., 1999; Lin et al., 2003). In vivo studies have demonstrated an increase in interstitial collagenase mRNA in the gingiva of dogs undergoing orthodontic tooth movement (Redlich et al., 2001). Increases in the levels of interstitial collagenase have also been detected at day 7 of the OTM cycle at the sites of bone and root resorption (Domon et al., 1999).

Because of the importance of MMPs in bone remodeling, they represent a potential target for pharmacological manipulation. Several peptidomimetic hydroxymates are available that serve as "suicide substrates" for MMPs (Schultz et al., 1992). The purposes of this project were to test whether orthodontic tooth movement can be inhibited by the localized delivery of an MMP inhibitor and to provide data supporting RGDpeptide production by MMP activity as a possible underlying mechanism.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents
The peptidomimetic hydroxymate MMP inhibitor SC44463 (Ki vs. rodent interstitial collagenase 0.65 nM (Holliday et al., 1997) and its ineffective optical isomer 44201 (Ki > 200 nM vs. rodent interstitial collagenase) were obtained from Monsanto (St. Louis, MO, USA). Ilomastat (GM6001; galardin), a potent broad-spectrum peptidomimetic hydroxymate MMP (Ki for numerous MMPs < 1 nM) inhibitor, was obtained from BioMol (Plymouth Meeting, PA, USA). Recombinant fibroblast growth factor-2 (FGF-2) was a kind gift of Louis Avioli (Washington University, St. Louis, MO, USA). Human recombinant parathyroid hormone (1–34) (PTH) was obtained from Peninsula (San Carlos, CA, USA). Cacitriol was obtained from BioMol. The peptide GRGDSP was from Gibco. Other reagents were purchased from Sigma (St. Louis, MO, USA) unless otherwise noted.

Mouse Marrow Cultures
Osteoclast-containing mouse marrow cultures were obtained as described previously (Holliday et al., 1995). The University of Florida Institutional Care and Usage Committee approved the mouse protocol (project #0706). Four- to six-week-old Swiss-Webster mice (Harlan, Indianapolis, IN, USA) were killed by cervical dislocation. Femurs and tibias were dissected free of adherent tissue. We expelled the bone marrow by cutting both bone ends and flushing the marrow cavity with {alpha}-modified minimal medium (Sigma) plus 10% fetal bovine serum (HyClone Laboratories, Logan, UT, USA), using a 25-gauge needle. The marrow cells were washed twice and plated into either 24-well plates or tissue culture plates at a density of 1 x 108 cells per cm2. Cultures were stimulated with calcitriol (10 nM), parathyroid hormone (PTH) (100 ng/mL), or basic fibroblast growth factor (bFGF) (600 pM). Cells were fed and fresh stimulant added on the 3rd day in culture, and on the 6th day, cultures were washed and loaded onto slices of sperm whale dentin as described (Holliday et al., 1995).

Assays for Bone Resorption
Bone resorption was determined by scanning electron microscopy (Holliday et al., 1995). Marrow from mouse marrow cultured for 6 days as described above was mechanically scraped from tissue culture plates and loaded onto 1-cm2 slices of sperm whale dentin slices in 24-well plates. In some experiments, the dentin slices were coated with the peptide GRGDSP (0.1 mg/mL) in water for 8 hrs. The coated slices were then washed extensively with {alpha}MEM plus 10% fetal bovine serum (the standard culture medium), then incubated overnight prior to loading of the marrow. Cultures were incubated on dentin slices for 4 days with continued stimulation with calcitriol, PTH, or bFGF as described above. In some cases, incubation was performed in the presence of either SC44463 or SC44201 (10 µM). After the culture period, bone slices were prepared for scanning electron microscopy as described (Holliday et al., 1995). The amount of surface area resorbed was quantified from a grid of 50-µM squares placed over photographs of 3 random fields taken with no tilt angle from at least 3 bone slices. Grid intersections over pits were counted and expressed as a percentage of total intersections. Pits were counted as contiguous excavations, regardless of the number of facets.

Rat Preparation and Surgical Insertion of Polymers Containing Ilomastat
Ilomastat (GM6001, Galardin) was delivered adjacent to the maxillary molars by incorporation into the polymer ELVAX 40. The polymer containing the peptide was prepared based on a published protocol (Langer and Folkman, 1976). A 2.63-mg quantity of Ilomastat was mixed with 100 µL of 10% ELVAX 40 (Dupont, Wilmington, DE, USA). The resulting dispersion was quick-frozen on dry ice, then dried under a vacuum to remove solvent. The resultant material was cut into strips (1 mm height x 3 mm length). Strips of ELVAX 40 or ELVAX 40 impregnated with Ilomastat were surgically inserted into the palatal mucosa adjacent to the first molar.

Animals for OTM Experiments
The University of Florida Institutional Care and Usage Committee approved all rat protocols (project #C341). Male Sprague-Dawley rats (from 40 to 50 days old) were purchased from Charles River Breeding Laboratories (Wilmington, MA, USA) and were allowed to acclimate for 2 wks, under experimental conditions. This included being maintained on a standard 12-hour light/dark cycle, being fed a diet of ground laboratory chow, and having access to distilled water ad libitum. We chose young male rats to eliminate the hormonal changes associated with estrus.

Orthodontic Tooth Movement
During the experimental period, animal weight was monitored. Anesthesia was attained by means of intra-peritoneal injections of ketamine (87 mg/kg) and xylazine (13 mg/kg). Three weeks before the initiation of tooth movement, the rats underwent a preparatory session that consisted of the bonding of modified orthodontic cleats bilaterally to the occlusal surfaces of the maxillary first molars, pinning the maxillary incisors to prevent further eruption, reducing the height of the mandibular incisors, and extracting the mandibular first molars to prevent appliance damage.

OTM was accomplished as described (King et al., 1991), with the rats positioned in a head restrainer and the placement of orthodontic spring-activated appliances. One end of a nickel titanium closed-coil spring (light; #10-000-06; GAC, Central Islip, NY, USA) was ligated to the molar cleat while the other was attached to a 40-gram suspended weight. This force was chosen since it has been shown to demonstrate the typical OTM kinetics and acceptable balance between bone formation and resorption. The anterior end of the coil was then bonded with autocuring methacrylate to the acid-etched lateral surface of the maxillary incisors, followed by removal of the weight and excess coil spring. This method ensured a precise and reproducible initial orthodontic force designed both to tip the maxillary first molars mesially, and to provide appliances with equivalent decay rates. The strain environments created were primarily compression on the mesial surface and tension on the distal. The control group received all procedures except spring placement.

Measurement of Tooth Movement
Four cephalometric x-rays of the head were taken at day 0 and at days 1, 3, 7, and 10. Radiographic exposures were made with the use of a head-holding device consisting of ear rods for positioning the rat face down on the base. The cephalograms were then digitized at 600 dpi with useo of the NIH imaging program ImageJ. OTM was measured from the molar cleat to the distal of the pin on the incisor.

Statistical Analysis
Data from the pitting assays were expressed as means ± SEM and analyzed by one-tailed Student’s t test. Tooth movement at each time point was determined as the average from the 4 cephalograms. The data for tooth movement and drift were expressed as means ± SEM. A one-way analysis of variance (ANOVA) was used for testing the significance between the groups.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Osteoclasts were produced by mouse marrow cultures in response to several stimuli. We showed that calcitriol, PTH, and bFGF induce bone resorption by marrow cultures. Blocking matrix metalloproteinases disrupted osteoclastic bone resorption in cultures stimulated with calcitriol, PTH, or bFGF (Fig. 1Go).



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  		Figure 1. Bone resorption triggered by various agents is sensitive to inhibition by the matrix metalloproteinase inhibitor 44463, but not its ineffective stereo-isomer, 44201. The data are expressed as the mean ± SE (n = 4). The asterisk indicates p < 0.05 using Student’s t test.

 
MMP Activity May Expose Cryptic RGD Sequences
Dentin slices were coated with a short RGDcontaining peptide that has been shown to interact with the vitronectin receptor (Ruoslahti and Pierschbacher, 1987). Pre-coating dentin slices with the RGD peptide resulted in normal levels of bone resorption by the marrow cultures in the presence an MMP inhibitor (Fig. 2Go). Control dentin slices pre-coated with an RGE peptide failed to rescue bone resorption in the presence of MMP inhibitors.



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  		Figure 2. Pre-coating dentin slices with a short RGD-containing peptide rescues bone resorption by mouse marrow from inhibition by the matrix metalloproteinase inhibitor 44463. Mouse marrow osteoclasts were grown in the presence of 10 nM calcitriol for 6 days. Dentin slices were coated with either an RGD-containing peptide or vehicle as described in MATERIALS & METHODS. The marrow cultures were loaded onto the coated or uncoated dentin slices in the presence of the matrix metalloproteinase inhibitor 44463 or its ineffective stereo-isomer, 44201. After 5 days, the dentin slices were prepared for scanning electron microscopy. (A) The bar graph presents quantitative analysis of the experiment. The data are expressed as the mean ± SE (n = 4). The asterisk indicates p < 0.05 using Student’s t test. (B–E) Representative electron micrographs from the experiment described above. (B) Uncoated dentin slice, control inactive MMPI; (C) uncoated dentin slice, plus active MMPI; (D) RGDcoated dentin slice, inactive MMPI; and (E) RGD-coated dentin slice, active MMPI. The size bar for B–E equals 25 µM.

 
Orthodontic Tooth Movement Studies on Young Male Rats
The control untreated animals demonstrated the 3 phases of orthodontic tooth movement: initial tipping, lag phase, and then tooth movement (Rygh and Reitan, 1972) (Fig. 3Go). The timing and extent of tooth movement in control animals were similar to those observed previously under the same conditions (King et al., 1991). In the presence of Ilomastat, tooth movement at day 10 was significantly inhibited. Initial tipping and the lag phase were not significantly different.



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  		Figure 3. Tooth movement kinetics in the control or Ilomastat-treated rats. Each point represents the mean ± SEM of 5–7 animals. A one-way analysis of variance (ANOVA) was used for testing the significance between the groups. *p < 0.01.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Blocking the activity of MMPs inhibits bone resorption by mouse marrow osteoclasts triggered by calcitriol by preventing mature osteoclasts from activating (Holliday et al., 1997, 2003). Rodent interstitial collagenase activity is required for this inhibition. Using the same marrow culture system, we showed that MMP activity was also required to stimulate osteoclast activity in response to parathyroid hormone and fibroblast growth factor-2. Coating bone slices with RGD peptides allowed bone resorption to occur in the presence of an MMP inhibitor. The MMP inhibitor Ilomastat limited orthodontic tooth movement when delivered locally in ELVAX 40. Analysis of these data provides a "proof in principle" for the use of locally delivered MMP inhibitors in facilitating orthodontic procedures, and suggests a role for integrin-ligands produced as the result of MMP activity.

Although several laboratories have found that MMPs are required for osteoclastic bone resorption, there is considerable discussion regarding their precise role (Delaisse et al., 2000). In addition to interstitial collagenase, the MT1-MMP and MMP-9 have been implicated in osteoclastic activity (Sato et al., 1997; Engsig et al., 2000). MMP-9 knockout mice exhibit deficiencies in their ability to recruit osteoclasts during early bone development (Engsig et al., 2000). MT1-MMP knockout mice have skeletal defects, but these result from failures in soft-tissue turnover during morphogenesis rather than from effects on the mature bone remodeling cycle (Holmbeck et al., 1999). Interstitial collagenase activity triggers osteoclasts to activate (Holliday et al., 1997, 2003). In vivo experiments show that interstitial collagenase activity on collagen is required for PTH-stimulated bone resorption in mice (Zhao et al., 1999). Osteoclast activation involves the formation of a unique actin-based structure called the actin ring, which is associated with the sealing zone that segregates the extracellular resorption compartment (King and Holtrop, 1975) and the transport of vacuolar H+-ATPase to the ruffled membrane—a specialized domain of the osteoclast plasma membrane that apposes the resorption compartment (Blair et al., 1989). Both re-organizations of the osteoclast require the activity of interstitial collagenase (Holliday et al., 2003). Our finding that RGD peptides can substitute for MMP activity is consistent with both interstitial collagenase cleaving collagen to expose RGD sequences and data indicating a vital role for {alpha}vß3 integrin in osteoclast activation (McHugh et al., 2000; Feng et al., 2001). However, during orthodontic tooth movement, MMP inhibitors likely affect osteoblasts and other cells involved in orthodontic tooth movement (Shiga et al., 2003).

As we have shown, coating an RGD peptide onto a dentin slice can be pro-resorptive, while the same peptide given in a soluble form is strongly inhibitory (Fisher et al., 1993). Osteoclasts may require a directional integrin signal to organize for resorption. RGD, coated onto a dentin slice, or cleaved type I collagen associated with the dentin stimulates the apical surface of the osteoclast only, while soluble RGD peptide uniformly stimulates the osteoclast surface, disrupting osteoclast polarization.

The use of implantable polymers for the sustained release of drugs was pioneered by Judah Folkman (Folkman et al., 1966). Recently, the contraceptive Norplant was developed based on this concept (Darney, 1994). ELVAX 40 is a non-biodegradable that has been used to deliver biologically active substances in significant quantities over time in several other experimental paradigms (Li et al., 1991). Ilomastat is a broad-spectrum inhibitor that has been shown to inhibit osteoclastic activity associated with osteolytic lesions associated with bone tumors (Winding et al., 2002). The local delivery of Ilomastat by ELVAX 40 proved effective at inhibiting orthodontic tooth movement. Initial tipping, which is mainly due to compression of the periodontal ligament and bone bending, was observed in both groups, as was a lag phase. During this lag phase (days 3–7), it is known that osteoclasts are recruited to the pressure side of the tooth (King et al., 1991; Rody et al., 2001). Recruitment involves migration of osteoclast precursors from the marrow, then fusion of the precursors and activation of the osteoclasts. This process takes several days (Rody et al., 2001). Resorption of alveolar bone by osteoclasts then accommodates tooth movement. The finding that tooth movement between Day 7 and Day 10 was blocked is therefore consistent with Ilomastat blocking osteoclastic resorption. However, it is also likely that blocking MMPs affects cell types other than osteoclasts that are involved in OTM.


   ACKNOWLEDGMENTS
 
This work was supported by NIH grants DE13857 to C.D. and AR47959 to L.S.H and by an American Association of Orthodontists Foundation grant (LSH).

Received August 15, 2002; Last revision April 7, 2003; Accepted June 6, 2003


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