Biodegradable Nanoflowers with Abaloparatide Spatiotemporal Management of Functional Alveolar Bone Regeneration.

Post-extraction alveolar bone atrophy greatly hinders the subsequent orthodontic tooth movement (OTM) or implant placement. In this study, we synthesized biodegradable bifunctional bioactive calcium phosphorus nanoflowers (NFs) loaded with abaloparatide (ABL), namely ABL@NFs, to achieve spatiotemporal management for alveolar bone regeneration. The NFs exhibited a porous hierarchical structure, high drug encapsulation efficacy, and desirable biocompatibility. ABL was initially released to recruit stem cells, followed by sustained release of Ca2+ and PO43- for in situ interface mineralization, establishing an osteogenic "biomineralized environment". ABL@NFs successfully restored morphologically and functionally active alveolar bone without affecting OTM. In conclusion, the ABL@NFs demonstrated promising outcomes for bone regeneration under orthodontic condition, which might provide a desirable reference of man-made "bone powder" in the hard tissue regeneration field.

Macrophage M2 polarization promotes pulpal inflammation resolution during orthodontic tooth movement.

Mechanical force induces hypoxia in the pulpal area by compressing the apical blood vessels of the pulp, triggering pulpal inflammation during orthodontic tooth movement. However, this inflammation tends to be restorable. Macrophages are recognized as pivotal immunoreactive cells in the dental pulp. Whether they are involved in the resolution of pulpal inflammation in orthodontic teeth remains unclear. In this study, we investigated macrophage polarization and its effects during orthodontic tooth movement. It was demonstrated that macrophages within the dental pulp polarized to M2 type and actively participated in the process of pulpal inflammation resolution. Inflammatory reactions were generated and vascularization occurred in the pulp during orthodontic tooth movement. Macrophages in orthodontic pulp show a tendency to polarize towards M2 type as a result of pulpal hypoxia. Furthermore, by blocking M2 polarization, we found that macrophage M2 polarization inhibits dental pulp-secreting inflammatory factors and enhances VEGF production. In conclusion, our findings suggest that macrophages promote pulpal inflammation resolution by enhancing M2 polarization and maintaining dental health during orthodontic tooth movement.

miR-20a: a key regulator of orthodontic tooth movement via BMP2 signaling pathway modulation.

AIM: In this study, we aimed to establish a rat tooth movement model to assess miR-20's ability in enhancing the BMP2 signaling pathway and facilitate alveolar bone remodeling. METHOD: 60 male SD rats had nickel titanium spring devices placed between their left upper first molars and incisors, with the right side serving as the control. Forces were applied at varying durations (18h, 24h, 30h, 36h, 42h, 1d, 3d, 5d, 7d, 14d), and their bilateral maxillary molars and surrounding alveolar bones were retrieved for analysis. Fluorescent quantitative PCR was conducted to assess miR-20a, BMP2, Runx2, Bambi and Smad6 gene expression in alveolar bone, and western blot was performed to determine the protein levels of BMP2, Runx2, Bambi, and Smad6 after mechanical loading. RESULT: We successfully established an orthodontic tooth movement model in SD rats and revealed upregulated miR-20a expression and significantly increased BMP2 and Runx2 gene expression and protein synthesis in alveolar bone during molar tooth movement. Although Bambi and Smad6 gene expression did not significantly increase, their protein synthesis was found to decrease significantly. CONCLUSION: MiR-20a was found to be involved in rat tooth movement model alveolar bone remodeling, wherein it promoted remodeling by reducing Bambi and Smad6 protein synthesis through the BMP2 signaling pathway.

Applications of nanotechnology in orthodontics: a comprehensive review of tooth movement, antibacterial properties, friction reduction, and corrosion resistance.

Nanotechnology has contributed important innovations to medicine and dentistry, and has also offered various applications to the field of orthodontics. Intraoral appliances must function in a complex environment that includes digestive enzymes, a diverse microbiome, mechanical stress, and fluctuations of pH and temperature. Nanotechnology can improve the performance of orthodontic brackets and archwires by reducing friction, inhibiting bacterial growth and biofilm formation, optimizing tooth remineralization, improving corrosion resistance and biocompatibility of metal substrates, and accelerating or decelerating orthodontic tooth movement through the application of novel nanocoatings, nanoelectromechanical systems, and nanorobots. This comprehensive review systematically explores the orthodontic applications of nanotechnology, particularly its impacts on tooth movement, antibacterial activity, friction reduction, and corrosion resistance. A search across PubMed, the Web of Science Core Collection, and Google Scholar yielded 261 papers, of which 28 met our inclusion criteria. These selected studies highlight the significant benefits of nanotechnology in orthodontic devices. Recent clinical trials demonstrate that advancements brought by nanotechnology may facilitate the future delivery of more effective and comfortable orthodontic care.

Effect of orthodontic space closure on dental pulp sensitivity. Prospective clinical trial.

BACKGROUND: Orthodontic tooth movement (OTM) is a biological process that can influence the function of the pulp, including its innervation. The excitability of the nerve fibres of the pulp may be altered by forces exerted on the nerve fibres or by reduced blood flow to the pulp. The aim of this clinical study was to evaluate the sensitivity of the dental pulp during levelling and during the phase of space closure, to assess the role of certain controlled risk factors. METHODS: Twenty-two adolescent participants requiring orthodontic space closure in transcanine sector were enrolled in a prospective clinical study. Patients were observed before OTM, after levelling and 1 month during active space closure. The sensitivity threshold of the pulp was measured using the electric pulp test (EPT). Dental models were obtained using an intraoral scanner, allowing measurement of interdental distances and calculation of OTM speed. The teeth were categorized according to position and tooth type. RESULTS: The EPT values increased significantly during orthodontic treatment (one-way RM-ANOVA, P = .014). There was a significant difference in EPT values between the tooth categories. Teeth with a single root adjacent to the residual space had the highest EPT thresholds (two-way RM-ANOVA, P < .001; Holm-Sidak, P < .05). CONCLUSIONS: OTM reduced pulpal sensitivity. Pulpal sensitivity during active space closure was similar to sensitivity during the levelling phase. The pulpal sensitivity of molars was less affected by OTM than that of single-rooted teeth, while teeth closer to the gap had a significantly higher pulpal sensitivity threshold during active OTM.

Small nucleolar RNA host gene 5 plays a role in orthodontic tooth movement by inhibiting osteoclast differentiation.

BACKGROUND AND OBJECTIVES: The alveolar bone remodelling promoted by reasonable mechanical force triggers orthodontic tooth movement (OTM). The generation of osteoclasts is essential in this process. However, the mechanism of mechanical force mediating osteoclast differentiation remains elusive. Small nucleolar RNA host gene 5 (SNHG5), which was reported to mediate the osteogenic differentiation of bone marrow mesenchymal stem cells in our previous study, was downregulated in human periodontal ligament cells (hPDLCs) under mechanical force. At the same time, the RANKL/OPG ratio increased. Based on this, we probed into the role of SNHG5 in osteoclast formation during OTM and the relevant mechanism. MATERIALS AND METHODS: SNHG5 and the RANKL/OPG ratio under different compressive forces were detected by western blotting (WB) and qRT-PCR. Impact of overexpression or knockdown of SNHG5 on osteoclast differentiation was detected by qRT-PCR, WB and transwell experiments. The combination of SNHG5 and C/EBPß was verified by RNA immunoprecipitation and RNA pull-down assays. The expression of SNHG5 and osteoclast markers in gingiva were analysed by qRT-PCR and the paraffin sections of periodontal tissues were used for histological analysis. RESULTS: Compressive force downregulated SNHG5 and upregulated the RANKL/OPG ratio in hPDLCs. Overexpression of SNHG5 inhibited RANKL's expression and osteoclast differentiation. SNHG5 combined with C/EBPß, a regulator of osteoclast. The expression of SNHG5 in periodontal tissue decreased during OTM. CONCLUSION: SNHG5 inhibited osteoclast differentiation during OTM, achieved by affecting RANKL secretion, which may provide a new idea to interfere with bone resorption during orthodontic treatment.

Clinical and preclinical evidence on the bioeffects and movement-related implications of photobiomodulation in the orthodontic tooth movement: A systematic review.

Photobiomodulation (PBM) has been demonstrated as a non-invasive and painless technique with great potential to accelerate orthodontic tooth movement (OTM). However, there is a great inconsistency among PBM protocols and reported outcomes, probably due to the poor translatability of preclinical knowledge into early clinical practice. Hence, this review aims to fill this gap by establishing the state-of-the-art on both preclinical and clinical applications of PBM, and by comprehensively discussing the most suitable stimulation protocols described in the literature. This review was conducted according to PRISMA guidelines. A bibliographic search was carried out in the PubMed, Scopus and Cochrane databases using a combination of keywords. Only studies written in English were eligible and no time limit was applied. A total of 69 studies were selected for this review. The revised literature describes that PBM can effectively reduce orthodontic treatment time and produce analgesic and anti-inflammatory effects. We found that PBM of 640 ± 25, 830 ± 20 and 960 ± 20 nm, delivered at a minimum energy density per irradiation point of 5 J/cm2 daily or every other day sessions is robustly associated with increased tooth movement rate. Pain relief seems to be achieved with lower irradiation doses compared to those required for OTM acceleration. For the first time, the bioeffects induced by PBM for the acceleration of OTM are comprehensively discussed from a translational point of view. Collectively, the evidence from preclinical and clinical trials supports the use of PBM as a coadjuvant in orthodontics for enhancing tooth movement and managing treatment-associated discomfort. Overall, the revised studies indicate that optimal PBM parameters to stimulate tissue remodelling are wavelengths of 830 ± 20 nm and energy densities of 5-70 J/cm2 applied daily or every other day can maximize the OTM rate, while lower doses (up to 16 J/cm2 per session) delivered in non-consecutive days seem to be optimal for inducing analgesic effects. Future research should focus on optimizing laser parameters and treatment protocols customized for tooth and movement type. By fine-tuning laser parameters, clinicians can potentially reduce treatment times, improve patient comfort and achieve more predictable outcomes, making orthodontic care more efficient and patient-friendly, thus consolidating PBM usage in orthodontics.

The effect of light compressive and tensile mechanical forces on SOST and POSTN expressions in human periodontal ligament cells: an in vitro study.

Periodontal ligament (PDL) cells play an important role in mechanosensing and secretion of signaling molecules during bone remodeling. However, the regulatory mechanism is unknown. The aim of the present study is to investigate the expression pattern of periostin and sclerostin in response to orthodontic forces in periodontal ligament cells in vitro. PDL cells were isolated from extracted teeth and treated with compressive forces of 25 gr/cm2 or equiaxial tension forces at frequency 1 Hz for 0, 24, 48, and 72 h. qRT-PCR was applied to evaluate the gene expressions. The secretion of sclerostin and periostin was assessed using ELISA. DAPI staining was used to evaluate apoptosis. The expression of sclerostin elevated significantly at protein and gene levels under compression forces after 24 h, while the application of tensile forces induced the expression of periostin and its upstream regulator RUNX2 (p < 0.05). Gene expression up-regulation was significant for POSTN and RUNX2 after 48 and 72 h tensile forces. Also, the gene expression of sclerostin reduced in a time-dependent manner after application of tensile force. The compression forces enhanced apoptosis to 7.5 ± 3.5% and induced gene expression of apoptotic markers of CASP9, and BCL2 within 72 h of exposure. Periostin and sclerostin play an important role in orthodontic loads and their expressions are affected oppositely by compressive and tensile forces that might be suggested as a biomarker for assessment of bone remodeling during orthodontic treatment.

Correlation of salivary cytokine IL-17A and 1,25 dihydroxycholecalciferol in patients undergoing orthodontic treatment.

The management of malocclusion has developed greatly in terms of treatment simulation and biomechanics, but treatment duration has been a great concern to the clinician as well as the patient. 1-25dihydroxycholecalciferol (biologically active form of Vitamin D) stimulates both osteoclasts and osteoblasts and was found to be the most significant in Orthodontic Tooth Movement acceleration. Inflammatory cytokines like IL-17A also play an important role in osteoclastogenesis and can enhance the rate of Orthodontic Tooth Movement.To perform a simultaneous evaluation of pro-inflammatory salivary cytokine IL-17A and salivary 1-25dihydroxycholecalciferol and to correlate their role on orthodontic tooth movement.A prospective cohort study was conducted among n = 97 patients. Saliva samples were collected from the patients at three phases of the orthodontic treatment, centrifuged and stored at 4℃ for evaluation of salivary 1-25dihydroxycholecalciferol levels and Pro-inflammatory cytokine IL-17A using ELISA.The mean salivary 1-25dihydoxycholecalciferol levels were 41.250 ng/ml, 33.246 ng/ml and 35.043 ng/ml during the initial phase, lag phase and post lag phase of orthodontic treatment. The mean pro-inflammatory cytokine IL-17 A levels were 107.79 pg/ml, 102.98 pg/ml and 66.156 pg/ml during the initial phase, lag phase and post lag phase of orthodontic treatment. There was a correlation between the salivary 1-25dihydroxycholecalciferol level and salivary cytokine IL-17A levels during the various phases of orthodontic treatment using Spearman's correlation rho test and linear regression analysis. There was no significant difference (p > 0.05) between 1-25dihydroxycholecalciferol levels and gender during the various phases (initial phase, lag phase and post lag phase) of Orthodontic treatment.There was a negative correlation between salivary 1-25dihydroxycholecalciferol level and salivary cytokine IL-17A levels during the various phases of orthodontic treatment. The level of 1-25dihydroxycholecalciferol and salivary cytokine IL-17A have been quantified during the various phases of Orthodontic treatment and this can be used clinically for the supplementation of Vitamin D in patients with low vitamin D levels and can enhance the treatment duration for the patient with less damaging effects to the surrounding tissues.

NF-κB Decoy Oligodeoxynucleotide-Loaded Poly Lactic-co-glycolic Acid Nanospheres Facilitate Socket Healing in Orthodontic Tooth Movement.

Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following the bilateral extraction of maxillary first molars in a controlled experiment involving forty rats of OTM model with ethics approved. The decreased tendency of the OTM distance and inclination angle with increased bone volume and improved trabecular bone structure indicated minimized alveolar bone destruction. Reverse transcription-quantitative polymerase chain reaction and histomorphometric analysis demonstrated the suppression of inflammation and bone resorption by downregulating the expression of tartrate-resistant acid phosphatase, tumor necrosis factor-α, interleukin-1ß, cathepsin K, NF-κB p65, and receptor activator of NF-κB ligand while provoking periodontal regeneration by upregulating the expression of alkaline phosphatase, transforming growth factor-ß1, osteopontin, and fibroblast growth factor-2. Importantly, relative gene expression over the maxillary second molar compression side in proximity to the alveolus highlighted the pharmacological effect of intra-socket PLGA-NfD administration, as evidenced by elevated osteocalcin expression, indicative of enhanced osteocytogenesis. These findings emphasize that locally administered PLGA-NfD serves as an effective inflammatory suppressor and yields periodontal regenerative responses following tooth extraction.

Correlation of sex hormone levels with orthodontic tooth movement in the maxilla: a prospective cohort study.

BACKGROUND: Sex hormones secreted during the menstrual cycle and the application of orthodontic forces to teeth can affect the metabolism of periodontal ligaments. This study aimed to determine whether there are any differences in orthodontic tooth displacement during the menstrual cycle and when using hormonal contraceptives and whether the amount of female sex hormones influences the efficiency of tooth displacement. METHODS: A total of 120 women aged between 20 and 30 years with Angle Class II requiring transpalatal arch (TPA) to derotate teeth 16 and 26 were included in this study. The participants were divided into two groups: group A, which included women with regular menstruation, and control group B, which included women taking monophasic combined oral contraceptives. Group A was divided into subgroups according to the moment of TPA activation: menstruation (A1), ovulation phase (A2), and luteal phase (A3) (examination I). On intraoral scans, measurement points were marked on the proximal mesial cusps of teeth 16 and 26, and the intermolar distance (M1) was determined. The change in the position of the measurement points 6 weeks after activation (examination II) made it possible to determine the derotating extent of teeth 16 (O16) and 26 (O26) and the widening of the intermolar distance (M2-M1). In examinations I and II, tooth mobility in the alveoli was assessed using Periotest based on the periotest values (PTV) PTV1 and PTV2, respectively. RESULTS: A significant difference in all parameters was observed among groups A1, A2, and A3 (P < 0.001). Group A3 showed the highest values of parameters O16, O26, and M2-M1, and group A2 showed the lowest values, which did not differ from the control group (P = 0.64). PTV2 and PTV1 were the highest in group A3 and the lowest in groups A1 and B. Intergroup differences were statistically significant (P < 0.001). CONCLUSIONS: With the quantification of changes in tooth mobility in the alveoli during the menstrual cycle in women undergoing orthodontic treatment, it was possible to determine that female sex hormones affect the effectiveness of orthodontic treatment, and the optimal moment for TPA activation is the luteal phase of the menstrual cycle.

Impact of concentrated growth factor (CGF) injection on acceleration of orthodontic tooth movement in rabbits.

BACKGROUND: The present study aimed to assess how a concentrated growth factor (CGF) injection affects the rate of orthodontic tooth movement in rabbits. METHODS: This experimental investigation employed a split-mouth configuration. Before orthodontic mesialization of the maxillary first molars, CGF was prepared and administered using submucosal injections on the buccal and palatal sides of the maxillary first molars in one randomly assigned quadrant. The opposite quadrant was used as a control. The study examined four time points:1, 2, 3, and 4 weeks. The measurement of tooth movement was conducted at each follow-up point using a digital caliper. The rabbits were euthanized, and their maxillary segments, specifically the maxillary first molars, were studied histologically to identify any alterations occurring on both the tension and compression sides. RESULTS: Significant tooth movement was observed in the experimental sides versus control sides in the second, third, and fourth week of follow-up periods (p ≤ 0.05). Histologically, on the compression side, the CGF group showed bone resorption and periodontal ligament active reactions from the first week and continued throughout the next three weeks. Also, on the tension side, the CGF group depicted cementoblastic and osteoblastic activities from the first week followed by fibroblastic activities from the second week and all activities continued till the fourth week. CONCLUSIONS: CGF has the potential to effectively enhance orthodontic tooth movement without adverse clinical or histological effects.

The effect of chewing gum on the rate of en-masse space closure: A randomised controlled trial.

AIM: To evaluate the effect of chewing gum on the rate of space closure, oral hygiene, pain during space closure and appliance breakage in patients undergoing fixed appliance therapy. DESIGN: A prospective, single-centre, two-arm, parallel, double-blinded randomised controlled trial. SETTING: Orthodontic unit of a privately funded hospital, Chennai, India. PARTICIPANTS: In total, 28 participants were randomly allocated into a chewing gum group (CGG) (n = 14) or a control group (CG) (n = 14). METHODS: Baseline data were collected at the start of retraction (T0), at 4 weeks (T1), 8 weeks (T2) and 12 weeks (T3) after the start of retraction. Rate of space closure, pain, oral hygiene and appliance breakage were assessed at T1, T2 and T3. Data were analysed using an independent t-test with P < 0.05 considered to be statistically significant. RESULTS: The mean rate of space closure in the CGG was 0.9 ± 0.2 mm/month and 0.8 ± 0.2 mm/month in the CG (P = 0.07, 95% confidence intervals [CI] were 0.80-1.01 for the CGC and 0.70-0.91 for the CG). In both the groups, oral hygiene became worse between T0 and T3. At T0 and T1, participants in the CGG reported less pain at 24 h and 7 days when compared to the CG (P < 0.05). At T2 and T3, participants in the CGG reported less pain at 0 h, 24 h and 7 days when compared to the CG (P < 0.05). Appliance breakage in both groups was minimal, with an odds ratio of 0.7 (95% CI 0.1-3.8) and was similar (P = 0.66). CONCLUSION: There was minimal increase that was clinically not significant in the rate of space closure with chewing gum. Chewing gum ensured better oral hygiene, helped alleviate pain and had no effect on appliance breakage during space closure.

Targeting phosphatidylinositol-3-kinase for inhibiting maxillary bone resorption.

Previous studies have suggested a role of phosphatidylinositol-3-kinase gamma (PI3Kγ) in bone remodeling, but the mechanism remains undefined. Here, we explored the contribution of PI3Kγ in the resorption of maxillary bone and dental roots using models of orthodontic tooth movement (OTM), orthodontic-induced inflammatory root resorption, and rapid maxillary expansion (RME). PI3Kγ-deficient mice (PI3Kγ-/- ), mice with loss of PI3Kγ kinase activity (PI3KγKD/KD ) and C57BL/6 mice treated with a PI3Kγ inhibitor (AS605240) and respective controls were used. The maxillary bones of PI3Kγ-/- , PI3KγKD/KD , and C57BL/6 mice treated with AS605240 showed an improvement of bone quality compared to their controls, resulting in reduction of the OTM and RME in all experimental groups. PI3Kγ-/- mice exhibited increased root volume and decreased odontoclasts counts. Consistently, the pharmacological blockade or genetic deletion of PI3K resulted in increased numbers of osteoblasts and reduction in osteoclasts during OTM. There was an augmented expression of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (Alp), a reduction of interleukin-6 (Il-6), as well as a lack of responsiveness of receptor activator of nuclear factor kappa-Β (Rank) in PI3Kγ-/- and PI3KγKD/KD mice compared to control mice. The maxillary bones of PI3Kγ-/- animals showed reduced p-Akt expression. In vitro, bone marrow cells treated with AS605240 and cells from PI3Kγ-/- mice exhibited significant augment of osteoblast mineralization and less osteoclast differentiation. The PI3Kγ/Akt axis is pivotal for bone remodeling by providing negative and positive signals for the differentiation of osteoclasts and osteoblasts, respectively.

GCN5 regulates ZBTB16 through acetylation, mediates osteogenic differentiation, and affects orthodontic tooth movement.

In the process of orthodontic tooth movement (OTM), periodontal ligament fibroblasts (PDLFs) must undergo osteogenic differentiation. OTM increased the expression of Zinc finger and BTB domain-containing 16 (ZBTB16), which is implicated in osteogenic differentiation. Our goal was to investigate the mechanism of PDLF osteogenic differentiation mediated by ZBTB16. The OTM rat model was established, and PDLFs were isolated and exposed to mechanical force. Hematoxylin-eosin staining, Alizarin Red staining, immunofluorescence, and immunohistochemistry were carried out. The alkaline phosphatase (ALP) activity was measured. Dual-luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted. In OTM models, ZBTB16 was significantly expressed. Additionally, there was an uneven distribution of PDLFs in the OTM group, as well as an increase in fibroblasts and inflammatory infiltration. ZBTB16 interference hindered PDLF osteogenic differentiation and decreased Wnt and ß-catenin levels. Meanwhile, ZBTB16 activated the Wnt/ß-catenin pathway. ZBTB16 also enhanced the expression of the osteogenic molecules osterix, osteocalcin (OCN), osteopontin (OPN), and bone sialo protein (BSP) at mRNA and protein levels. The interactions between Wnt1 and ZBTB16, as well as GCN5 and ZBTB16, were also verified. The adeno-associated virus-shZBTB16 injection also proved to inhibit osteogenic differentiation and reduce tooth movement distance in in vivo tests. ZBTB16 was up-regulated in OTM. Through acetylation modification of ZBTB16, GCN5 regulated the Wnt/ß-catenin signaling pathway and further mediated PDLF osteogenic differentiation.

Role of noncoding RNAs in orthodontic tooth movement: new insights into periodontium remodeling.

Orthodontic tooth movement (OTM) is biologically based on the spatiotemporal remodeling process in periodontium, the mechanisms of which remain obscure. Noncoding RNAs (ncRNAs), especially microRNAs and long noncoding RNAs, play a pivotal role in maintaining periodontal homeostasis at the transcriptional, post-transcriptional, and epigenetic levels. Under force stimuli, mechanosensitive ncRNAs with altered expression levels transduce mechanical load to modulate intracellular genes. These ncRNAs regulate the biomechanical responses of periodontium in the catabolic, anabolic, and coupling phases throughout OTM. To achieve this, down or upregulated ncRNAs actively participate in cell proliferation, differentiation, autophagy, inflammatory, immune, and neurovascular responses. This review highlights the regulatory mechanism of fine-tuning ncRNAs in periodontium remodeling during OTM, laying the foundation for safe, precise, and personalized orthodontic treatment.

Osteocyte Mechanotransduction in Orthodontic Tooth Movement.

PURPOSE OF REVIEW: Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone. Since osteocytes are significant in mechanotransduction and orchestrate osteoclast and osteoblast activity, they likely play a central role in orthodontic tooth movement. In this review, we attempt to shed light on the impact and role of osteocyte mechanotransduction during orthodontic tooth movement. RECENT FINDINGS: Mechanically loaded osteocytes produce signaling molecules, e.g., bone morphogenetic proteins, Wnts, prostaglandins, osteopontin, nitric oxide, sclerostin, and RANKL, which modulate the recruitment, differentiation, and activity of osteoblasts and osteoclasts. The major signaling pathways activated by mechanical loading in osteocytes are the wingless-related integration site (Wnt)/ß-catenin and RANKL pathways, which are key regulators of bone metabolism. Moreover, osteocytes are capable of orchestrating bone adaptation during orthodontic tooth movement. A better understanding of the role of osteocyte mechanotransduction is crucial to advance orthodontic treatment. The optimal force level on the periodontal tissues for orthodontic tooth movement producing an adequate biological response, is debated. This review emphasizes that both mechanoresponses and inflammation are essential for achieving tooth movement clinically. To fully comprehend the role of osteocyte mechanotransduction in orthodontic tooth movement, more knowledge is needed of the biological pathways involved. This will contribute to optimization of orthodontic treatment and enhance patient outcomes.

Mechanical force induces macrophage-derived exosomal UCHL3 promoting bone marrow mesenchymal stem cell osteogenesis by targeting SMAD1.

BACKGROUND: Orthodontic tooth movement (OTM), a process of alveolar bone remodelling, is induced by mechanical force and regulated by local inflammation. Bone marrow-derived mesenchymal stem cells (BMSCs) play a fundamental role in osteogenesis during OTM. Macrophages are mechanosensitive cells that can regulate local inflammatory microenvironment and promote BMSCs osteogenesis by secreting diverse mediators. However, whether and how mechanical force regulates osteogenesis during OTM via macrophage-derived exosomes remains elusive. RESULTS: Mechanical stimulation (MS) promoted bone marrow-derived macrophage (BMDM)-mediated BMSCs osteogenesis. Importantly, when exosomes from mechanically stimulated BMDMs (MS-BMDM-EXOs) were blocked, the pro-osteogenic effect was suppressed. Additionally, compared with exosomes derived from BMDMs (BMDM-EXOs), MS-BMDM-EXOs exhibited a stronger ability to enhance BMSCs osteogenesis. At in vivo, mechanical force-induced alveolar bone formation was impaired during OTM when exosomes were blocked, and MS-BMDM-EXOs were more effective in promoting alveolar bone formation than BMDM-EXOs. Further proteomic analysis revealed that ubiquitin carboxyl-terminal hydrolase isozyme L3 (UCHL3) was enriched in MS-BMDM-EXOs compared with BMDM-EXOs. We went on to show that BMSCs osteogenesis and mechanical force-induced bone formation were impaired when UCHL3 was inhibited. Furthermore, mothers against decapentaplegic homologue 1 (SMAD1) was identified as the target protein of UCHL3. At the mechanistic level, we showed that SMAD1 interacted with UCHL3 in BMSCs and was downregulated when UCHL3 was suppressed. Consistently, overexpression of SMAD1 rescued the adverse effect of inhibiting UCHL3 on BMSCs osteogenesis. CONCLUSIONS: This study suggests that mechanical force-induced macrophage-derived exosomal UCHL3 promotes BMSCs osteogenesis by targeting SMAD1, thereby promoting alveolar bone formation during OTM.

Impact of PIEZO1-channel on inflammation and osteoclastogenesis mediated via periodontal ligament fibroblasts during mechanical loading.

The identification of mechanosensitive ion channels and their importance in innate immunity provides new starting points to elucidate the molecular mechanisms of orthodontic tooth movement. The mechanosensitive electron channel PIEZO1 (Piezo Type Mechanosensitive Ion Channel Component 1) may play a crucial role in orthodontic tooth movement. To investigate the role of the PIEZO1 channel, periodontal ligament fibroblasts (PDLF) were subsequently treated with a PIEZO1 inhibitor (GsMTx) with simultaneous pressure application or with an activator (JEDI2) without mechanical strain. The expression of genes and proteins involved in orthodontic tooth movement was examined by RT-qPCR, Western blot and ELISA. In addition, the effect on PDLF-mediated osteoclastogenesis was investigated in a coculture model using human monocytes. Inhibition of PIEZO1 under pressure application caused a reduction in RANKL (receptor activator of NF-kB ligand) expression, resulting in decreased osteoclastogenesis. On the other hand, activation of PIEZO1 without mechanical strain downregulated OPG (osteoprotegerin), resulting in increased osteoclastogenesis. PIEZO1 appears to play a role in the induction of inflammatory genes. It was also shown to influence osteoclastogenesis.

Dynamic changes in transcriptome during orthodontic tooth movement.

OBJECTIVES: The objective of this study was to determine global changes in gene expression with next generation sequencing (NGS) in order to assess the biological effects of orthodontic tooth movement (OTM) on alveolar bone in a rat model. MATERIALS AND METHODS: Thirty-five Wistar rats (age 14 weeks) were used in the study. The OTM was performed using closed coil Nickel-Titanium spring to apply a mesial force on maxillary first molars of 8-10 g. Three hours, 1, 3, 7 and 14 days after the placement of the appliance, rats were killed at each time point respectively. The alveolar bone, around left maxillary first molar, were excised on compression side. The samples were immediately frozen in liquid nitrogen for subsequent RNA extraction. Total RNA samples were prepared for mRNA sequencing using the Illumina kit. RNA-Seq reads were aligned to the rat genomes using the STAR Aligner and bioinformatic analysis was performed. RESULTS: A total of 18 192 genes were determined. Day 1 has the highest number of differentially expressed genes (DEGs) observed with more upregulated than downregulated genes. A total of 2719 DEGs were identified to use as input for the algorithm. Six distinct clusters of temporal patterns were observed representing proteins that were differentially regulated indicating different expression kinetics. Principal component analysis (PCA) showed distinct clustering by time points and days 3, 7 and 14 share similar gene expression pattern. CONCLUSIONS: Distinct gene expression pattern was observed at different time points studied. Hypoxia, inflammation and bone remodelling pathways are major mechanisms behind OTM.