Local administration of ReveromycinA ointment suppressed alveolar bone loss in mice.

ReveromycinA (RMA) was developed and is a unique agent for inhibiting osteoclast activity. In a previous study, we experimentally induced periodontal disease in a high-turnover osteoporosis osteoprotegerin-knockout mice (OPG KO) model and found that intraperitoneal administration of RMA inhibited alveolar bone resorption. We prepared a novel RMA-containing ointment for topical non-invasive administration in the oral cavity, in preparation for possible future clinical application. And we investigated whether this ointment can inhibit alveolar bone resorption in an experimental mouse model of periodontal disease. We examined wild-type (WT) and OPG KO mice ligated with wire around contact points on the left first and second molars to cause food impaction and induce experimental periodontal disease. RMA was administered three times a day. Using micro-computed tomography, we measured the volume of alveolar bone loss and also performed histological analysis. Our findings showed that localized administration of RMA containing ointment resulted in suppressed alveolar bone resorption, reduced osteoclast count, and lower immunostaining scores of inflammation sites compared with controls in both OPG KO and WT mice. Localized application of the specific osteoclast suppressor RMA in ointment form in the oral cavity could be a novel treatment for periodontitis that inhibits alveolar bone resorption locally.

Guanabenz inhibits alveolar bone resorption in a rat model of periodontitis.

Increase of sympathetic activity has been known to exacerbate osteoporosis through promotion of bone resorption. However, it is largely unknown about involvement of sympathetic activity in exacerbation of periodontitis. In this study, we investigated whether α2-adrenergic receptor (α2-AR) agonist guanabenz which decreases sympathetic activity, attenuates alveolar bone resorption in rats having high sympathetic activity with periodontitis. Volumes of residual alveolar bone and attachment levels in periodontium were examined using micro-computed tomography and hematoxylin-eosin staining, respectively. Furthermore, osteoclast numbers per bone surface and osteoclast surface per bone surface were measured using tartrate-resistant acid phosphatase staining. To examine the suppressive effects of guanabenz on pro-inflammatory cytokines, expression levels of tyrosine hydroxylase (TH), TNF-α, IL1-ß, and IL-6 in periodontium were measured using immunohistostaining. Administration of guanabenz attenuated loss of alveolar bone and attachment levels in rats having high sympathetic activity. Furthermore, its administration suppressed osteoclast numbers in rats having high sympathetic activity. TH, TNF-α, IL-1ß, and IL-6 positive cells in periodontium in rats treated with guanabenz for 12 weeks, were lower than those in control rats having high sympathetic activity. This study demonstrated administration of α2-AR agonist guanabenz attenuates alveolar bone resorption through decrease of sympathetic activity in rats.

UV Light-Generated Superhydrophilicity of a Titanium Surface Enhances the Transfer, Diffusion and Adsorption of Osteogenic Factors from a Collagen Sponge.

It is a significant challenge for a titanium implant, which is a bio-inert material, to recruit osteogenic factors, such as osteoblasts, proteins and blood effectively when these are contained in a biomaterial. The objective of this study was to examine the effect of ultraviolet (UV)-treatment of titanium on surface wettability and the recruitment of osteogenic factors when they are contained in an atelocollagen sponge. UV treatment of a dental implant made of commercially pure titanium was performed with UV-light for 12 min immediately prior to the experiments. Superhydrophilicity on dental implant surfaces was generated with UV-treatment. The collagen sponge containing blood, osteoblasts, or albumin was directly placed on the dental implant. Untreated implants absorbed only a little blood from the collagen sponge, while the UV-treated implants absorbed blood rapidly and allowed it to spread widely, almost over the entire implant surface. Blood coverage was 3.5 times greater for the UV-treated implants (p < 0.001). Only 6% of the osteoblasts transferred from the collagen sponge to the untreated implants, whereas 16% of the osteoblasts transferred to the UV-treated implants (p < 0.001). In addition, a weight ratio between transferred albumin on the implant and measured albumin adsorbed on the implant was 17.3% in untreated implants and 38.5% in UV-treated implants (p < 0.05). These results indicated that UV treatment converts a titanium surface into a superhydrophilic and bio-active material, which could recruite osteogenic factors even when they were contained in a collagen sponge. The transfer and subsequent diffusion and adsorption efficacy of UV-treated titanium surfaces could be useful for bone formation when titanium surfaces and osteogenic factors are intervened with a biomaterial.

Does local injection of reveromycin A inhibit tooth movement without causing systemic side effects?

OBJECTIVE: To determine the feasibility of local inhibition of osteoclast activity and control of tooth movement with local intraoral reveromycin A (RMA) injection in model mice for experimental tooth movement. MATERIALS AND METHODS: Eight-week-old wild-type mice (n = 6 per group) were divided into four groups consisting of two non-RMA groups that received normal saline for 14 (14-day non-RMA group) or 21 consecutive days (21-day non-RMA group) and 2 RMA groups that received RMA (1.0 mg/kg of weight) for 14 (14-day RMA group) or 21 consecutive days (21-day RMA group). RMA was injected locally into the buccal mucosa of the left first maxillary molar twice daily starting 3 days before placement of the 10-gf Ni-Ti closed coil spring. Tooth movement distance was analysed using micro-computed tomography. The effects on surrounding alveolar bone were evaluated by measuring the ratio of bone surface area to tissue surface area with haematoxylin-eosin-stained sections and counting the number of osteoclasts in periodontal tissue with TRAP-stained sections. Blood tests were performed and bone volume and trabecular separation at the tibial neck were measured to analyse systemic side effects. RESULTS: Local RMA injection inhibited tooth movement by 40.6 per cent, promoted alveolar bone volume maintenance by 37.4 per cent, and inhibited osteoclast activity around the tooth root at 21 days by 40.8 per cent. Systemic effects on osteoclasts or osteoblasts were not observed. CONCLUSION: Local injection of RMA enabled control of tooth movement without systemic side effects in a mouse model.

Tuning of Titanium Microfiber Scaffold with UV-Photofunctionalization for Enhanced Osteoblast Affinity and Function.

Titanium (Ti) is an osteoconductive material that is routinely used as a bulk implant to fix and restore bones and teeth. This study explored the effective use of Ti as a bone engineering scaffold. Challenges to overcome were: (1) difficult liquid/cell infiltration into Ti microfiber scaffolds due to the hydrophobic nature of Ti; and (2) difficult cell attachment on thin and curved Ti microfibers. A recent discovery of UV-photofunctionalization of Ti prompted us to examine its effect on Ti microfiber scaffolds. Scaffolds in disk form were made by weaving grade 4 pure Ti microfibers (125 µm diameter) and half of them were acid-etched to roughen the surface. Some of the scaffolds with original or acid-etched surfaces were further treated by UV light before cell culture. Ti microfiber scaffolds, regardless of the surface type, were hydrophobic and did not allow glycerol/water liquid to infiltrate, whereas, after UV treatment, the scaffolds became hydrophilic and immediately absorbed the liquid. Osteogenic cells from two different origins, derived from the femoral and mandibular bone marrow of rats, were cultured on the scaffolds. The number of cells attached to scaffolds during the early stage of culture within 24 h was 3-10 times greater when the scaffolds were treated with UV. The development of cytoplasmic projections and cytoskeletal, as well as the expression of focal adhesion protein, were exclusively observed on UV-treated scaffolds. Osteoblastic functional phenotypes, such as alkaline phosphatase activity and calcium mineralization, were 2-15 times greater on UV-treated scaffolds, with more pronounced enhancement on acid-etched scaffolds compared to that on the original scaffolds. These effects of UV treatment were associated with a significant reduction in atomic carbon on the Ti microfiber surfaces. In conclusion, UV treatment of Ti microfiber scaffolds tunes their physicochemical properties and effectively enhances the attachment and function of osteoblasts, proposing a new strategy for bone engineering.

Novel Osteogenic Behaviors around Hydrophilic and Radical-Free 4-META/MMA-TBB: Implications of an Osseointegrating Bone Cement.

Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.

Alteration of tooth movement by reveromycin A in osteoprotegerin-deficient mice.

INTRODUCTION: Osteoprotegerin-deficient mice develop severe high-turnover osteoporosis with porous low-density trabecular bone from an age-related increase in osteoclast activity and are useful alveolar bone models of osteoporosis or frail periodontal tissue. Bisphosphonate (BP), a first-line drug for osteoporosis, is bone-avid, causing side effects such as brittle and fragile bones and jaw osteonecrosis after tooth extraction. In orthodontics, active movement is precisely controlled by temporarily suppressing and resuming movement. BP impedes such control because of its long half-life of several years in bone. Therefore, we investigated the novel osteoclast-specific inhibitor reveromycin A (RMA), which has a short half-life in bone. We hypothesized that tooth movement could be precisely controlled through temporary discontinuation and re-administration of RMA. METHODS: Osteoprotegerin-deficient mice and wild-type mice were developed as tooth movement models under constant orthodontic force. A constant orthodontic force of 10 g was induced using a nickel-titanium closed coil spring to move the maxillary first molar for 14 days. We administered BP (1.25 mg/kg) or RMA (1.0 mg/kg) continuously and then discontinued it to reveal how the subsequent movement of teeth and surrounding alveolar bone was affected. RESULTS: Continuous BP or RMA administration suppressed osteoclast activity and preserved alveolar bone around the roots, apparently normalizing bone metabolism. Tooth movement remained suppressed after BP discontinuation but resumed at a higher rate after discontinuation of RMA. CONCLUSIONS: RMA appears useful for controlling orthodontic tooth movement because it can be suppressed and resumed through administration and discontinuation, respectively.

Insertion torque and Periotest values are important factors predicting outcome after orthodontic miniscrew placement.

INTRODUCTION: Approximately 14% of orthodontic anchor screws (miniscrews) become dislodged regardless of the accuracy of placement. It is therefore important to investigate the factors causing dislodgement. We evaluated the stability of miniscrews after placement to identify factors influencing outcome in orthodontic treatment using miniscrews. METHODS: We investigated 120 miniscrews (Dual-top Auto Screw III; Jeil Medical, Seoul, Korea) (diameter, 1.4 mm; length, 6 mm) placed on the buccal or lingual side between the maxillary second premolar and the first molar in women. Patient age and rate and time of screw dislodgement were examined. Insertion torque values and Periotest (Tokyo Dental Industrial, Tokyo, Japan) measurements indicating horizontal and vertical mobility of the inserted screws were compared between groups with and without dislodgement (failure and success groups, respectively). RESULTS: Mean insertion torque values were 10.7 ± 1.9 N·cm and 8.5 ± 2.1 N·cm in the failure and success groups, respectively. Cortical bone thickness measurements (success group, 1.34 ± 0.35 mm; failure group, 0.99 ± 0.09 mm) were significantly higher, whereas Periotest values at placement (success group, horizontal, 4.9 ± 1.4; vertical, 4.7 ± 1.3; failure group, horizontal, 7.0 ± 0.8; vertical, 7.1 ± 0.9) were significantly lower in the success group than in the failure group. CONCLUSIONS: The Periotest value, together with insertion torque and cortical bone thickness, could serve as an index of initial stability for predicting the outcome of miniscrew placement.

Adult skeletal Class II high-angle case treated with a fully customized lingual bracket appliance.

To achieve optimum occlusal and facial results in a patient with high-angle maxillary protrusion, it is important to move Point A back with retraction of the anterior teeth and prevent clockwise rotation of the mandible through good vertical control. A woman, aged 42 years 5 months, with a protrusive profile sought lingual orthodontic treatment. She had a skeletal Class II high-angle pattern with maxillary protrusion and mandibular retrusion. The extraction of the 4 first premolars was indicated to correct the problems. The vertical bowing effect, a side effect known to occur with conventional lingual bracket systems owing to torque loss, would preclude adequate retraction of Point A and compromise the facial results. To prevent this issue, a fully customized lingual bracket system with vertical slots for the anterior teeth using ribbon-wise archwires was selected. A midpalatal miniscrew was used to prevent molar extrusion. As a result, the bodily retraction of the maxillary incisors and Point A was achieved, obtaining an attractive facial profile.

Ultraviolet photofunctionalization increases removal torque values and horizontal stability of orthodontic miniscrews.

INTRODUCTION: The objective of this study was to examine the effects of ultraviolet-mediated photofunctionalization of miniscrews and the in-vivo potential of bone-miniscrew integration. METHODS: Self-drilling orthodontic miniscrews made from a titanium alloy were placed in rat femurs. Photofunctionalization was performed by treating the miniscrews with ultraviolet light for 12 minutes with a photo device immediately before implantation. Maximum insertion torque (week 0), removal torque (weeks 0 and 3), and resistance to lateral tipping force (week 3) were examined. RESULTS: The removal torque at 3 weeks of healing was higher for the photofunctionalized screws than for the untreated screws. The regenerated bone tissue was more intact and contiguous around the photofunctionalized miniscrews than around the untreated ones. The miniscrew-bone complex seemed to produce interface failure, not cohesive fracture, in both groups. The displacement of untreated screws under a lateral tipping force was greater than that of photofunctionalized miniscrews. CONCLUSIONS: These results suggest that photofunctionalization increases the bioactivity of titanium-alloy miniscrews and improves the anchoring capability of orthodontic miniscrews, even without modification of the surface topography.

Effect of ultraviolet-mediated photofunctionalization for bone formation around medical titanium mesh.

PURPOSE: The new technology of photofunctionalization with ultraviolet (UV) light for titanium implants has earned considerable attention. We hypothesized that UV light treatment would enhance bone formation on titanium mesh. MATERIALS AND METHODS: We implemented in vitro and in vivo experiments to examine the effectiveness of UV treatment for bone formation on titanium mesh surfaces. Titanium mesh for medical use was prepared as samples, which were autoclaved and stored under dark ambient conditions for 4 weeks. UV treatment was performed for 12 minutes. Carbon contamination, hydrophilicity, and protein adhesion of the titanium mesh surface were examined in an in vitro model. Bone tissue formation around the titanium mesh was observed in a rat femur bone model. The Mann-Whitney U test was used to examine differences between the untreated and UV-treated groups. P values of < .05 were considered significant. RESULTS: UV-mediated photofunctionalization reduced carbon contamination rates on the untreated titanium mesh surfaces. The hydrophobic surface of the untreated titanium mesh became superhydrophilic after UV-mediated photofunctionalization (P < .01). The amount of protein adsorbed onto the titanium was 1.5 to 3 times greater on the photofunctionalized titanium mesh surfaces than on the untreated titanium mesh surfaces (P < .01). In the animal experiment, the newly formed bone on the UV-treated titanium mesh was approximately 2.5 times greater than that on the untreated mesh (P < .05). CONCLUSIONS: UV-mediated photofunctionalization is effective, as demonstrated by the enhanced bone tissue formation on the titanium mesh. Future studies will focus on bone augmentation using an UV-mediated photofunctionalized titanium implant and mesh.

Midpalatal miniscrews and high-pull headgear for anteroposterior and vertical anchorage control: cephalometric comparisons of treatment changes.

INTRODUCTION: Our aim was to evaluate which anchorage system is better suited for both anteroposterior and vertical anchorage control of maxillary posterior teeth. METHODS: Fifty-one subjects requiring maximum anchorage were divided into 2 groups according to maxillary posterior anchorage reinforcement: high-pull headgear, conventional transpalatal arch, and interarch elastics (n = 28); or modified transpalatal arch supported by 2 midpalatal miniscrews (n = 23). Bilateral maxillary first premolars were extracted in all patients. Pretreatment and posttreatment lateral cephalometric radiographs were superimposed to compare skeletal and dental changes between the groups. RESULTS: (1) The miniscrew group had less mesial movement of the maxillary first molars (0.85 vs 3.63 mm) and greater maxillary incisor retraction (6.87 vs 4.50 mm) than did the headgear group with the same treatment duration. (2) The maxillary molars were significantly intruded in the miniscrew group (1.30 mm), whereas they were extruded in the headgear group (0.71 mm). In the miniscrew group, intrusion of the maxillary molars resulted in a statistically significant decrease in the mandibular plane angle (0.80°). Patients using high-pull headgear showed no significant decrease in these measurements. CONCLUSIONS: In both the anteroposterior and vertical directions, a modified transpalatal arch supported by 2 midpalatal miniscrews provided more stable anchorage.

Stabilization of tooth movement by administration of reveromycin A to osteoprotegerin-deficient knockout mice.

INTRODUCTION: In this study, mechanical stress in the form of tooth movement was applied to osteoprotegerin-deficient knockout mice, which served as an animal model for juvenile Paget's disease. To compare and evaluate bone turnover and response of the surrounding bony tissue, we administered reveromycin A. We also investigated the ability of reveromycin A to control osteoclastic activity in juvenile Paget's disease. METHODS: Eight-week-old male osteoprotegerin-deficient knockout and wild-type mice were injected with reveromycin A (15 mg/kg of body weight) intraperitoneally twice daily. An elastic module was inserted interproximally between the maxillary left first and second molars. RESULTS: Administration of reveromycin A to osteoprotegerin-deficient knockout mice reduced tooth movement distances, increased bone volumes at the interradicular septum, decreased osteoclast counts, and reduced serum alkaline phosphatase and tartrate resistant acid phosphatase. Reveromycin A administration also caused a temporal shift in peak Runx2 staining in osteoprotegerin-deficient knockout mice so that the overall staining time course was similar to that observed for wild-type mice. CONCLUSIONS: Reveromycin A administration in osteoprotegerin-deficient knockout mice inhibited bone resorption and normalized bone formation. As a result, normal bone turnover was obtained.

Dynamics and observations of long-term orthodontic tooth movement and subsequent relapse in C57BL/6 mice.

The risk of relapse associated with orthodontic treatment is a major problem. Despite extensive research and discussion regarding the risk of orthodontic relapse, the underlying mechanisms remain to be elucidated. This study aimed to evaluate relapse following orthodontic treatment in mice (C57BL/6) tested via the coil spring method based on tooth movement at 21 days and mechanical retention at 7 days after completion of the procedure. During the experiment, relapse was observed and evaluated over 7 days. At the end of orthodontic tooth movement, the average distance was 259.6 (± 10.9) µm, and tooth movement was observed in all mice. No significant differences in distance were observed at the end of the experimental treatment period or after 7 days of mechanical retention. The distance at the start of observation was 258.6 (± 10.4) µm, whereas that at the end was 155.4 (± 12.4) µm, indicating that the distance had decreased significantly. Relative to the total relapse distance over the 7-day period, 45.7 (± 4.3)% of the relapse was observed on Day 0-1. The mouse model established in the current study provides an effective and reproducible method for the optimal evaluation of relapse. Our findings clarified that most of the relapse occurs within 7 days during the initial observation stage.

A case of skeletal maxillary protrusion with high angle and gummy smile treated with anchor screws.

This report discusses a case of a 20 year and 7-month-old female patient with a skeletal maxillary protrusion with gummy smile, crowding, and high angle due to horizontal protrusion of the maxillary anterior teeth. The gummy smile in this case was improved by an upward movement of the occlusal plane associated with maxillary molar intrusion and sufficient lingual movement while performing maxillary anterior teeth intrusion. Following treatment, it was stable even after 8 years of retention. Thus, it is important to ascertain the cause of gummy smile, and establish whether it is due to the vertical maxillary excess in the maxillary anterior teeth, or the horizontal protrusion of the maxillary anterior teeth.

Effective approach for improving a gummy smile : Upward movement of the maxillary occlusal plane using midpalatal miniscrews and a modified transpalatal arch.

PURPOSE: Correction of a gummy smile by orthodontic treatment alone has recently become feasible with the use of miniscrews. However, the optimal treatment mechanics remain unclear. Here we cephalometrically evaluated jaw and tooth displacement in cases where a gummy smile was improved using a level anchorage system (LAS). METHODS: Sixteen patients underwent orthodontic treatment using an LAS consisting of a modified transpalatal arch and midpalatal miniscrews. Cephalometric pretreatment and posttreatment measurements were compared using the paired t­test to determine significant skeletal and dental changes. The Mann-Whitney U test was used for nonparametric data. Spearman's rank correlation coefficient was used to evaluate correlations between different variables and the vertical change in prosthion position which was used to indicate the amount of gingival exposure. RESULTS: The changes noted after treatment were intrusion of the maxillary first molars (P < 0.001) combined with only minor extrusion of the mandibular first molars. Suppressed extrusion of the mandibular first molars was significantly correlated with greater upward movement of the prosthion (r = 0.676, P < 0.01). Upward movement of the prosthion was also significantly correlated with intrusion of the maxillary and mandibular incisors, anterior upward movement of the maxillary occlusal plane, and an increase of the SNP angle. CONCLUSIONS: Treatment involving the combined use of miniscrews and a modified transpalatal arch resulted in intrusion of the maxillary first molars and maxillary incisors and consequently elevated the maxillary occlusal plane. The results of this study suggest that intruding the maxillary occlusal plane and minimizing mandibular molar extrusion were effective to induce autorotation of the mandible and to improve a gummy smile.

Optimal sites for orthodontic anchor screw placement using panoramic images: risk of maxillary sinus perforation and contact with adjacent tooth roots during screw placement.

OBJECTIVES: This study investigated the safety of orthodontic anchor screw (OAS) placement by examining the morphology and degree of depression of the maxillary sinus adjacent to the alveolar bone between the maxillary molars. METHODS: We reviewed panoramic and CT imaging data of 25 patients. First, the morphology of the maxillary sinus adjacent to the alveolar bone between the maxillary molars on panoramic images was classified into three types: non-depressed sinus, funnel-like sinus depression, and sawtooth-like sinus depression. Then, the distance from the maxillary buccal bone to the maxillary sinus or to the maxillary lingual bone and the distance between the roots of the maxillary second premolar and first molar at heights of 5, 6.5, and 8 mm from the alveolar crest were measured on CT images and compared between the three sinus morphology groups. RESULTS: The sawtooth-like depression group had significantly smaller bone thickness than the other two groups, with mean thickness of < 4 mm at any height from the alveolar crest. The funnel-like depression and non-depression groups had mean bone thickness of > 8 mm at any height from the alveolar crest. CONCLUSIONS: Sawtooth-like sinus depression had increased risk of maxillary sinus perforation, suggesting that OAS placement in this region should be avoided. In contrast, OAS placement between 6.5 and 8 mm from the alveolar crest is advisable in patients with funnel-like sinus depression and at a site > 8 mm from the alveolar crest in those with a non-depressed sinus.

Effects of a ß2-adrenergic receptor blocker on experimental periodontitis in spontaneously hypertensive rats.

AIMS: Recent studies have reported a relationship between periodontal disease and hypertension, and previous evidence suggests that the sympathetic nervous system plays an important role in the control of bone metabolism. This study sought to evaluate the effect of the beta-2 adrenergic receptor (ß2-AR) blocker butoxamine on experimental periodontitis in a rat model. MATERIALS AND METHODS: Wistar-Kyoto and spontaneously hypertensive rats (n = 6 per group) were orally administered butoxamine 1 mg/kg/day and experimental periodontitis was induced by applying an orthodontic ligature wire. The rats were sacrificed after 4 weeks and the residual alveolar bone was measured using micro-computed tomography (micro-CT) imaging analysis software for histological analysis. KEY FINDINGS: Micro-CT imaging analysis showed a higher ratio of residual alveolar bone, BV/TV, and Tb.N in both Wistar-Kyoto and spontaneously hypertensive rats treated with butoxamine compared with the corresponding control rats. In histological analysis, compared with the Wistar-Kyoto and spontaneously hypertensive rat control groups, the corresponding butoxamine-treated groups showed a lower ratio of attachment level, lower values of osteoclast number and surface. SIGNIFICANCE: ß2-AR blockers maintained the alveolar bone mass and attachment level by suppressing osteoclast activity. Thus, ß2-AR blockers may be effective in preventing periodontitis.

Suppression of alveolar bone resorption by salubrinal in a mouse model of periodontal disease.

AIMS: The relationship between stress to endoplasmic reticulum (ER) and periodontitis has been known, and ER stress induced by Porphyromonas gingivalis results in the loss of alveolar bone. Salubrinal is a small synthetic compound and attenuates ER stress through inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined whether salubrinal attenuates periodontitis in a mouse model of experimental periodontal disease. MATERIALS AND METHODS: We evaluated loss of alveolar bone and attachment levels in periodontium using micro-computed tomography (µCT) and hematoxylin-eosin (HE) staining, respectively. Furthermore, we measured osteoclast numbers using tartrate-resistant acid phosphatase (TRAP) staining and osteoblast numbers using HE staining for bone resorption and for bone formation, respectively. To examine the inhibitory effects of salubrinal against pro-inflammatory cytokines, we measured TNF-α and IL1-ß score in periodontium using immunohistostaining. KEY FINDINGS: The results revealed that salubrinal suppressed loss of alveolar bone and attachment levels in periodontium induced by periodontitis. It decreased osteoclast numbers and increased osteoblasts. It also suppressed the expression levels of TNF-α in periodontium. SIGNIFICANCE: These results show that salubrinal alleviates periodontitis through suppression of alveolar bone resorption and the pro-inflammatory cytokine, and promotion of the bone formation. Since salubrinal has been shown to have these beneficial effects for periodontal disease, it may provide a novel therapeutic possibility for the disease.

Bisphosphonate inhibits bone turnover in OPG(-/-) mice via a depressive effect on both osteoclasts and osteoblasts.

Osteoclast differentiation and functioning are strictly controlled by RANKL expressed on osteoblast membrane surfaces, but whether osteoclasts exert control over osteoblasts remains unclear. In the present study, we examined the effect of an osteoclast inhibitor, a bisphosphonate (BP), on the response of maxillary bone to mechanical stress in a high-turnover osteoporosis model (OPG(-/-) mice, a model of juvenile Paget disease). Mechanical stress was induced by use of orthodontic elastics to move the maxillary first molar. BP was administered once per day beginning 5 days before elastic insertion. Relative to wild type (WT), in the OPG(-/-) mice tooth movement distance was greater, resorption of the interradicular septum occurred to a greater extent, the osteoclast count was higher, and serum alkaline phosphatase (ALP) was higher. However, administration of BP to OPG(-/-) mice reduced tooth movement distance, increased bone volume at the interradicular septum, decreased the osteoclast count, and reduced serum ALP. BP administration also caused a temporal shift in peak Runx2 staining in OPG(-/-) mice, such that the overall staining time course was similar to that observed for WT mice. We conclude that BP administration not only inhibited osteoclast activity in OPG(-/-) mice but also systemically and locally inhibited osteoblast activity. It is possible that osteoclasts are able to exert some negative control over osteoblasts.