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An Anti-c-Fms Antibody Inhibits Orthodontic Tooth Movement
H. Kitaura1,*,
M. Yoshimatsu1,
Y. Fujimura1,
T. Eguchi1,
H. Kohara1,
A. Yamaguchi2 and
N. Yoshida1
1 Divisions of Orthodontic and Dentofacial Orthopedics, Department of Translational Medicine, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; and
2 Department of Oral Restitution, Section of Oral Pathology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
Correspondence: * corresponding author, kitaura{at}nagasaki-u.ac.jp
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ABSTRACT
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Orthodontic force induces osteoclastogenesis in vivo. It has recently been reported that administration of an antibody against the macrophage-colony-stimulating factor (M-CSF) receptor c-Fms blocks osteoclastogenesis and bone erosion induced by tumor necrosis factor- (TNF-) administration. This study aimed to examine the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and osteolysis in an orthodontic tooth movement model in mice. Using TNF receptor 1- and 2-deficient mice, we showed that orthodontic tooth movement was mediated by TNF-. We injected anti-c-Fms antibody daily into a local site, for 12 days, during mechanical loading. The anti-c-Fms antibody significantly inhibited orthodontic tooth movement, markedly reduced the number of osteoclasts in vivo, and inhibited TNF--induced osteoclastogenesis in vitro. These findings suggest that M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement mediated by TNF-.
Key Words: c-fms • osteoclast • orthodontics • mouse • TNF-
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INTRODUCTION
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Orthodontic tooth movement is achieved through repeated alveolar bone resorption on the pressure side and stimulation of new bone formation on the tension side. Several studies have shown that orthodontic force induces expression of tumor necrosis factor- (TNF-) and suggested that TNF- has an important role in orthodontic tooth movement (Lowney et al., 1995; Uematsu et al., 1996; Ogasawara et al., 2004). TNF- induces several biological responses via TNF receptor types 1 (TNFR1) and 2 (TNFR2), with each receptor capable of mediating distinct intracellular signals (MacEwan, 2002). We previously established an in vivo orthodontic tooth movement model in mice to explore the mechanism of mechanical loading-induced bone changes (Yoshimatsu et al., 2006). We investigated the role of TNF- in orthodontic tooth movement using TNFR1-deficient and TNFR2-deficient mice, respectively. It was shown that the amount of tooth movement in TNFR2-deficient mice was less than that in wild-type mice. These results suggested that TNF- plays an important role in mechanical loading-induced osteoclastogenesis and bone remodeling during orthodontic tooth movement (Yoshimatsu et al., 2006).
Osteoclasts are defined as tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells on the bone surface that are responsible for the resorption of bone during the process of bone remodeling. The formation of osteoclasts is dependent on macrophage-colony-stimulating factor (M-CSF) and the ligand for the receptor activator of necrosis factor  B (RANKL). Both M-CSF and RANKL are essential factors for osteoclast differentiation (Teitelbaum, 2000). In addition, TNF- has been reported to induce osteoclast differentiation from bone marrow macrophages in vitro (Azuma et al., 2000; Kobayashi et al., 2000; Kim et al., 2005). TNF- plays an important role in bone-erosive diseases, such as rheumatoid arthritis (Redlich et al., 2002), periodontal disease (Abu-Amer et al., 1997), periprosthetic bone loss (Merkel et al., 1999), and post-menopausal osteoporosis (Kimble et al., 1996). It has recently been reported that administration of an antibody against the M-CSF receptor c-Fms completely blocks osteoclastogenesis and bone erosion induced by TNF- administration or inflammatory arthritis (Kitaura et al., 2005). Because orthodontic tooth movement is also mediated by TNF-, we hypothesized that an anti-c-Fms antibody might block osteoclastogenesis and bone resorption at the pressure side of a tooth undergoing orthodontic tooth movement, and that, as a result, it would also inhibit orthodontic tooth movement.
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MATERIALS & METHODS
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Experimental Animals
All experimental procedures were approved by the Animal Welfare Committee of Nagasaki University. Wild-type mice (C57BL6/J) and TNFR1/TNFR2-deficient mice (Tnfrsf1atm1ImxTnfrsf1btm1Imx) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). Eight-week-old mice were used in this experiment.
Culture for Osteoclast Formation
Bone marrow macrophages were derived from bone marrow cells (Takeshita et al., 2000). Bone marrow macrophages (5 x 103) were cultured in 200 µL of culture medium containing M-CSF (100 ng/mL) and TNF- (50 ng/mL) in a 96-well plate. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 in air (see APPENDIX for detailed description of the method).
Experimental Tooth Movement
Mice were fitted with the orthodontic appliance described previously (Yoshimatsu et al., 2006). This consisted of a Ni-Ti closed-coil spring inserted between the upper incisors and the upper-left first molar, and fixed with a 0.1-mm stainless steel wire around both teeth by means of a dental adhesive agent (Superbond, Sunmedical Co., Shiga, Japan). We used the left maxillary molar in each mouse to study experimental tooth movement. According to the manufacturer’s database, the force level of the coil spring after activation is approximately 10 g.
Measurement of Distance of Tooth Movement
The mice were perfused with 10 mM phosphate-buffered saline (PBS) to replace their blood, and then perfused with and immersed in 4% paraformaldehyde for fixation following application of the orthodontic force. After removal of the maxillae, an individual tray, with dental hydrophilic vinyl polysiloxane impression material (Exafine, injection type, GC Co., Tokyo, Japan), was placed on the maxillary teeth for impressions. We evaluated the distance of tooth movement by measuring the distance between the first and the second molars in the impression, under a stereoscopic microscope (VH-7000, Keyence Co., Osaka, Japan) (see APPENDIX for detailed description of the method).
Preparation for Histological Observation
After fixation, maxillae were demineralized in 10% ethylene-diaminetetraacetic acid (EDTA) for 10 days at 4°C. The samples were processed and embedded in paraffin and sectioned at 4 µm. Transverse sections of the first molar region were prepared (see APPENDIX for detailed description of the method).
Administration of Anti-c-Fms Antibody
AFS98 is a rat monoclonal, anti-murine c-Fms antibody (IgG2a) that inhibits M-CSF-dependent colony formation and cell growth by blocking the binding of M-CSF to its receptor (Sudo et al., 1995). An AFS98 hybridoma was maintained in HyQ-CCM1 medium (Hyclone, Logan, UT, USA), and antibody was purified with Protein G (Sigma Chemical Co., St. Louis, MO, USA). Mice were injected daily for 12 days with 10 µg of the anti-c-Fms antibody in 20 µL of phosphate-buffered saline (PBS), or PBS alone as a vehicle control, into the buccal gingiva close to the upper-left first molar during orthodontic tooth movement, except in the experiments with indicated antibody concentrations.
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RESULTS
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TNF- Affects Osteoclastogenesis and Bone Resorption during Orthodontic Tooth Movement
We investigated whether TNF- affected mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement. We observed the distances of tooth movement in wild-type and TNFR1/TNFR2-deficient mice during the experimental period. Tooth movement occurred on day 2 in both groups. From days 4 to 8, no tooth movement was observed in either group. On day 10, the distance of tooth movement increased in wild-type mice, but not in TNFR1/TNFR2-deficient mice. On day 12, tooth movement increased in both groups, but the distance in TNFR1/TNFR2-deficient mice was significantly lower than that in wild-type mice (Fig. 1A ). We evaluated the numbers of osteoclasts in the mesial region of the periodontium of the distobuccal root of the upper-left first molars during tooth movement. Although the number of TRAP-positive osteoclasts increased gradually in all mice after application of the appliance, TNFR-deficient mice had significantly fewer TRAP-positive osteoclasts than wild-type mice on day 12 (Figs. 1B, 1C). Therefore, mechanical loading-induced osteoclastogenesis and orthodontic tooth movement were inhibited in TNFR1/TNFR2-deficient mice.
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Figure 1. Time-course of changes in the amount of tooth movement in wild-type mice and TNFR1/TNFR2-deficient mice. Histological images and numbers of TRAP-positive cells on the pressure side of the distobuccal root of the first molar during orthodontic tooth movement. (A) Changes in the amount of tooth movement in wild-type (closed square) and TNFR1/TNFR2-deficient (open circle) mice. Wild-type: n = 4 (2 days), 4 (4 days), 6 (6 days), 10 (10 days), 11 (12 days). TNFR1/TNFR2-deficient mice: n = 6 (2 days), 4 (4 days), 9 (6 days), 10 (10 days), 4 (12 days). (B) TRAP-stained transverse section of wild-type and TNFR1/TNFR2-deficient mice. (C) The number of TRAP-positive multinuclear cells in wild-type (black bar) and TNFR1/TNFR2-deficient (white bar) mice. Wild-type: n = 6. TNFR1/TNFR2-deficient mice: n = 4 each. *p < 0.05 by the Mann-Whitney U-test. Scale bar: 100 µm in (B). Results are expressed as means ± SD.
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The Anti-c-Fms Antibody Inhibits Orthodontic Tooth Movement by Inhibiting Osteoclastogenesis
We assessed the distances of tooth movement after injection of the anti-c-Fms antibody. The distances of tooth movement in mice injected with 10 µg or 50 µg of the anti-c-Fms antibody were significantly lower than those in PBS-injected mice on day 12 (Figs. 2A, 2B). We decided to use daily injection of 10 µg of anti-c-Fms antibody in subsequent experiments. Osteoclast differentiation was also evaluated histologically. TRAP staining was performed on transverse histological sections of the distobuccal root. On day 12, we assessed the patterns of TRAP staining in control mice, mechanically loaded mice, and mechanically loaded mice injected with anti-c-Fms antibody. TRAP activity was observed on the alveolar bone surface in the distal region of the periodontium, but no activity was observed in the mesial region of the periodontium in control mice. TRAP activity was found on the resorptive surface in the mesial region of the periodontium in mechanically loaded mice on day 12 (Figs. 2C, 2D). These results suggested that many osteoclasts were present at the pressure side during orthodontic tooth movement. In contrast, there was significantly less TRAP activity in the mesial region of the periodontium in the mechanically loaded mice injected with anti-c-Fms antibody associated with orthodontic tooth movement. This result showed that the anti-c-Fms antibody inhibited osteoclastogenesis. To evaluate the area in which this inhibitory effect of the anti-c-Fms antibody on osteoclastogenesis could be seen, we analyzed histological sections of the side opposite to the anti-c-Fms-injected side. TRAP activity on the alveolar bone surface in the distal region of the periodontium was evaluated. There was no difference in TRAP activity between PBS-injected and anti-c-Fms antibody-injected mice (Figs. 2E, 2F). Thus, the anti-c-Fms antibody had no effect on osteoclastogenesis on the side opposite to antibody injection in vivo.
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Figure 2. The anti-c-Fms antibody inhibited orthodontic tooth movement by inhibiting osteoclastogenesis, and had no effect on the side opposite the injection. Mice were injected daily with the anti-c-Fms antibody or PBS during orthodontic tooth movement. (A) Picture of tooth movement after mechanical loading for 12 days, with daily administration of PBS or anti-c-Fms antibody, and control. (B) The distance of tooth movement after mechanical loading for 12 days with daily administration of various doses of the anti-c-Fms antibody. n = 11 (0 µg), 9 (0.1 µg), 6 (1 µg), 5 (10 µg), and 5 (50 µg). (C) TRAP-stained horizontal section of tooth movement after mechanical loading for 12 days with daily administration of PBS or anti-c-Fms antibody and control. (D) The number of TRAP-positive multinuclear cells in control (1), or each mouse injected daily with PBS (2) or anti-c-Fms antibody (3) during orthodontic tooth movement. n = 4 each. (E) TRAP-stained transverse section of a tooth on the side opposite to the daily injection with PBS or anti-c-Fms antibody (10 µg) for 12 days. (F) The number of TRAP-positive multinuclear cells on the side opposite to the injection in mice injected daily with PBS (1) or anti-c-Fms antibody (2). n = 4 each. *p < 0.05 by the Mann-Whitney U-test. Scale bars: 1 mm in (B) and 100 µm in (C) and (E). Results are expressed as means ± SD.
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The Anti-c-Fms Antibody Inhibits TNF--induced Osteoclastogenesis in vitro
To determine the inhibitory effect of the anti-c-Fms antibody on TNF--induced osteoclastogenesis, we added increasing amounts of the antibody to cultures of wild-type bone marrow macrophages in the presence of M-CSF and TNF-, which induce osteoclastogenesis. After 3 days, we determined the numbers of osteo clasts. Osteoclast arrest occurred in the presence of anti-c-Fms ant ibody at a dose of 10 ng/mL (Figs. 3A, 3B). Thus, the anti-c-Fms antibody inhibited TNF--induced osteoclastogenesis in vitro.
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Figure 3. The anti-c-Fms antibody arrests osteoclastogenesis in vitro. (A) Bone marrow macrophages were cultured in the presence of M-CSF (100 ng/mL) and TNF- (50 ng/mL) with increasing amounts of anti-c-Fms antibody, for 3 days. Cells were stained for TRAP activity for the identification of osteoclasts. (B) Numbers of osteoclasts generated in wells containing various amounts of anti-c-Fms antibody. The numbers of osteoclasts were counted in 4 replicates. *p < 0.05 vs. 0 ng/mL by the Mann-Whitney U-test. Scale bar: 20 µm in (A). Results are expressed as means ± SD.
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DISCUSSION
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Since the discovery of the RANK-RANKL signal transduction pathway, RANKL has been thought to be essential for osteoclast differentiation. This is supported by the finding that RANKL-deficient mice show severe osteopetrosis and completely lack osteoclasts (Kong et al., 1999). However, it has also been reported that TNF- induces osteoclast formation in bone marrow macrophages in the absence of osteoblasts and stromal cells (Azuma et al., 2000; Kobayashi et al., 2000). Recently, it was reported that TNF- induces the formation of osteoclasts independently of RANKL, in the presence of TGF-β (Kim et al., 2005). By contrast, it has been shown that TNF- induces osteoclastogenesis, but in the presence of basal levels of RANKL (Lam et al., 2000). In this study, we also examined the effect of TNF- on osteoclastogenesis. Our results showed that osteoclasts were induced from bone marrow macrophages in the presence of TNF- and M-CSF. TNF--induced expression of the stromal cell product M-CSF in vivo has been reported (Kitaura et al., 2004, 2005). M-CSF increases the survival and longevity of osteoclast precursors and influences cytoskeletal organization of osteoclasts (Teitelbaum, 2000). Recently, an anti-c-Fms antibody was reported to inhibit RANKL-induced osteoclastogenesis in vitro and completely block pathological osteoclastogenesis and bone resorption induced by inflammatory arthritis or direct injection of TNF- (Kitaura et al., 2005). Therefore, M-CSF and c-Fms are clearly candidate therapeutic targets for inflammatory osteolysis mediated by TNF-.
It has been reported that orthodontic tooth movement increases the levels of TNF- in the gingival sulcus in humans (Lowney et al., 1995; Uematsu et al., 1996). To explore the role of TNF- signaling during orthodontic tooth movement, we applied our tooth movement model to TNFR1-deficient or TNFR2-deficient mice. The results showed that the distance of tooth movement in TNFR2-deficient mice was less than that in wild-type mice. In this study, to confirm that TNF- has a role in tooth movement, we used TNFR1/TNFR2-deficient mice. The distance of tooth movement differed significantly between wild-type and TNFR1/TNFR2-deficient mice on days 10 and 12. We confirmed that TNF- affected tooth movement. We decided that day 12 was the best day for observation in this experiment, because the total distance of tooth movement and the number of osteoclasts at the pressure side of the tooth undergoing movement were greatest on day 12. There was no significant difference between TNFR1/TNFR2-deficient mice and TNFR2-deficient mice (Yoshimatsu et al., 2006) on day 10, suggesting that there is no synergistic effect of TNFR1 and TNFR2. In a recent study, Chung et al. reported the application of 10 g of force to teeth by means of a Ni-Ti closed-coil spring in mice (Chung et al., 2007). They observed root resorption and root-resorbing osteoclasts at the pressure side of teeth undergoing movement. We also identified root resorption in several samples. One of the causes of root resorption during orthodontic tooth movement is considered to be excessive orthodontic force (Harris et al., 2006). Samples showing root resorption contained many root-resorbing osteoclasts. This finding suggested that the orthodontic force used in this study was excessive.
M-CSF is produced by mesenchymal cells, and its regulated secretion has physiological and pathological consequences for osteoclasts. The absence of estrogen in post-menopausal osteoporosis is due to enhanced bone resorption caused by increased production of M-CSF by marrow stromal cells (Srivastava et al., 1998). The level of M-CSF is increased in the serum of persons with rheumatoid arthritis who have severe ankylosing spondylitis (Yang et al., 2006), and in the synovial fluid around loose joint prostheses (Takei et al., 2000). These observations suggest that stromal-cell-produced M-CSF may be an important mediator of TNF--induced osteoclastogenesis. Indeed, it has been reported that TNF- induces M-CSF gene expression in stromal cells and increases the number of osteoclast precursors in vivo (Kitaura et al., 2005). We previously reported that immunohistochemical expression of TNF- in mice was identified at the pressure side of a tooth undergoing orthodontic tooth movement (Yoshimatsu et al., 2006). In the present study, we evaluated the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and the degree of bone resorption in an orthodontic tooth movement model. We found that the anti-c-Fms antibody inhibited mechanical loading-induced osteoclastogenesis and bone resorption mediated by TNF-. Thus, M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption in orthodontic tooth movement.
To evaluate the area involved in the inhibitory effect of the anti-c-Fms antibody on osteoclastogenesis, we analyzed histological sections from the side opposite the anti-c-Fms injection. There was no difference in osteoclastogenesis between PBS-injected and anti-c-Fms antibody-injected mice. This result suggested that the anti-c-Fms antibody affected only the local area of the injected site when the amount of antibody we used was injected.
Finally, the anti-c-Fms antibody could inhibit TNF--induced osteoclastogenesis in vitro. In our previous report, the same anti-c-Fms antibody inhibited RANKL-induced osteoclastogenesis in vitro (Kitaura et al., 2005). When 10 ng/mL anti-c-Fms antibody was used in vitro, the number of osteoclasts induced by RANKL decreased almost by half. However, TNF--induced osteoclastogenesis was almost completely inhibited when the same amount of anti-c-Fms antibody was used in vitro. We suggest that TNF--induced osteoclastogenesis is inhibited by the anti-c-Fms antibody more easily than is RANKL-induced osteoclastogenesis. In our previous in vivo study, the anti-c-Fms antibody appeared to exert a substantially greater impact on inflammation-induced osteoclastogenesis mediated by TNF- than on physiological osteoclastogenesis, since TRAP-expressing cells within the tibial metaphysis appeared to be abundant in both antibody-injected mice and control mice (Kitaura et al., 2005). Analysis of our data strongly suggests that the anti-c-Fms antibody inhibits TNF--induced osteoclastogenesis. Thus, M-CSF may mediate mechanical loading-induced osteoclastogenesis at the pressure side of teeth undergoing movement.
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ACKNOWLEDGMENTS
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This work was supported by a Grant for Scientific Research from the Ministry of Education, Science and Culture, Japan, and by the president’s discretionary fund of Nagasaki University.
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://jdr.iadrjournals.org/cgi/content/full/87/4/396/DC1.
Received for publication June 14, 2007.
Revision received December 16, 2007.
Accepted for publication January 7, 2008.
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Journal of Dental Research, Vol. 87, No. 4,
396-400 (2008)
DOI: 10.1177/154405910808700405
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ABSTRACT
INTRODUCTION
