Mesenchymal stem cell-derived exosomes: a potential cell-free therapy for orthodontic tooth stability management.

Orthodontic relapse (OR) occurs at a rate of over 70%. Retention is the current attempt at prevention, but it requires a considerable amount of time and cannot fully block OR. It's imperative to find a safe and effective method for managing post-orthodontic tooth stability. Periodontal bone remodeling is one crucial biological foundation of OR. Mesenchymal stem cell-derived exosomes (MSC-Exo) show promise in relapse management by regulating periodontal bone remodeling. MSC-Exo can prevent relapse by regulating periodontal ligament function, osteoclast activity, osteoblast differentiation, macrophage polarization, and periodontal microcirculation. In recent years, exosome-loaded hydrogels, which achieve controlled exosome release, have demonstrated efficacy in promoting bone regeneration and remodeling, offering promising prospects for OR management. This review aims to highlight the use of MSC-Exo-based therapy for preventing OR, offering new insights for future research focused on improving tooth stability and enhancing orthodontic anchorage.

Integrated bioinformatic analysis of protein landscape in gingival crevicular fluid unveils sequential bioprocess in orthodontic tooth movement.

BACKGROUND: The biological mechanisms driving orthodontic tooth movement (OTM) remain incompletely understood. Gingival crevicular fluid (GCF) is an important indicator of the periodontal bioprocess, providing valuable cues for probing the molecular mechanisms of OTM. METHODS: A rigorous review of the clinical studies over the past decade was conducted after registering the protocol with PROSPERO and adhering to inclusion criteria comprising human subjects, specified force magnitudes and force application modes. The thorough screening investigated differentially expressed proteins (DEPs) in GCF associated with OTM. Protein-protein interaction (PPI) analysis was carried out using the STRING database, followed by further refinement through Cytoscape to isolate top hub proteins. RESULTS: A comprehensive summarization of the OTM-related GCF studies was conducted, followed by an in-depth exploration of biomarkers within the GCF. We identified 13 DEPs, including ALP, IL-1ß, IL-6, Leptin, MMP-1, MMP-3, MMP-8, MMP-9, PGE2, TGF-ß1, TNF-α, OPG, RANKL. Bioinformatic analysis spotlighted the top 10 hub proteins and their interactions involved in OTM. Based on these findings, we have proposed a hypothetic diagram for the time-course bioprocess in OTM, which involves three phases containing sequential cellular and molecular components and their interplay network. CONCLUSIONS: This work has further improved our understanding to the bioprocess of OTM, suggesting biomarkers as potential modulating targets to enhance OTM, mitigate adverse effects and support real-time monitoring and personalized orthodontic cycles.

The age-related effects on orthodontic tooth movement and the surrounding periodontal environment.

Orthodontic treatment in adults is often related to longer treatment time as well as higher periodontal risks compared to adolescents. The aim of this review is to explore the influence of age-related chages on orthodontic tooth movement (OTM) from macro and micro perspectives. Adults tend to show slower tooth movement speed compared to adolescence, especially during the early phase. Under orthodontic forces, the biological responses of the periodontal ligament (PDL) and alveolar bone is different between adult and adolescents. The adult PDL shows extended disorganization time, increased cell senescence, less cell signaling and a more inflammatory microenvironment than the adolescent PDL. In addition, the blood vessel surface area is reduced during the late movement phase, and fiber elasticity decreases. At the same time, adult alveolar bone shows a higher density, as well as a reduced osteoblast and osteoclast activation, under orthodontic forces. The local cytokine expression also differs between adults and adolescents. Side-effects, such as excessive root resorption, greater orthodontic pain, and reduced pulpal blood flow, also occur more frequently in adults than in adolescents.

Evaluation of anchorage loss after en masse retraction in orthodontic patients with maxillary protrusion using friction vs frictionless mechanics: randomized clinical trial.

OBJECTIVES: To evaluate anchorage loss after en masse retraction in bimaxillary dentoalveolar protrusion patients using friction vs frictionless mechanics. MATERIALS AND METHODS: Thirty patients with bimaxillary dentoalveolar protrusion needing extraction of upper first premolars and en masse retraction with maximum anchorage were included in this two-arm, parallel, single-center, single-blinded randomized clinical trial with a 1:1 allocation ratio using fully sealed opaque envelopes. Friction group retraction utilized elastomeric power chain between miniscrews and hooks crimped mesial to upper canines on 17 × 25 stainless steel archwire. Frictionless group used customized T-loop springs loading upper first molars indirectly anchored to miniscrews. Activation was every 4 weeks until full retraction. The primary outcome assessed was anchorage loss evaluated at cusp tip and root apex of the first molar. First molar rotation, incisor tip and torque, and root resorption of anterior teeth were evaluated on digital models and cone beam computed tomography taken before and after space closure. RESULTS: Anchorage loss at crown of first molar was significantly more in frictionless group by 2.1 mm (95% CI = -0.4 to 3.5), (P = .014), while there was no significant difference in anchorage loss at root apex between groups. Significant mesial in molar rotation of 6.672° (95% CI = 12.2-21.2), (P = 0.02) was greater in the frictionless group. Both groups showed comparable tip, torque, and root resorption values. No severe harms were reported. There was mild gingival overgrowth and inflammation in the frictionless group due to T-loop irritation. CONCLUSIONS: Extra anchorage considerations are needed during en masse retraction when frictionless mechanics is implemented as higher anchorage loss and molar rotation were detected. No difference in tip, torque, and root resorption was observed.

Effectiveness of autologous leukocyte-platelet-rich fibrin on the rate of maxillary canine retraction, rotation, pain, and soft tissue healing: A split-mouth randomized controlled trial.

Objective: To assess the effectiveness of leukocyte-platelet-rich fibrin (L-PRF) compared with conventional treatment on canine retraction, rotation, pain, and soft tissue healing. Methods: Sixteen adult patients aged 18-25 years (10 females, and 6 males; mean age 22.25 ± 2.26 years) with Class I bimaxillary protrusion and Class II div 1 malocclusion participated in this single-center, split-mouth randomized controlled trial at the Orthodontics Department of a single hospital in SCB Dental College and Hospital, Cuttack, India. Randomization was performed using a computer-assisted function with a 1:1 allocation ratio. The intervention included the placement of L-PRF on the experimental side and follow-up for 90 days. The primary outcome measures were canine retraction, rotation, pain, and soft tissue healing. The range of tooth movement was evaluated at 15-day intervals: 0th day (T0), 15th day (T1), 30th day (T2), 45th day (T3), 60th day (T4), 75th day (T5), and 90th day (T6). Canine rotation was assessed at T0 and T6, and pain and soft tissue healing were evaluated on the 3rd, 7th, and 15th days of the treatment. Results: Cumulatively, the L-PRF group demonstrated a significantly greater tooth movement as compared to conventional treatment group (P < 0.001). Overall, canine retraction was 1.5 times greater on the L-PRF side than on the control side. Canine rotation showed no significant relationship, whereas pain and soft tissue healing were significantly better on the L-PRF side than on the control side. Conclusions: Local administration of L-PRF amplifies canine retraction while improving pain and soft tissue repair.

Assessing the Effect of Exogenous Melatonin on Orthodontic Tooth Movement.

OBJECTIVE: To examine the effect of orthodontic tooth movement on experimental Wistar rats by synthesizing melatonin formulation for administration and conducting serological analysis of alkaline phosphatase (ALP) and melatonin, along with histological evaluation and immunohistochemistry analysis of ALP and interleukin-6 (IL-6) in both control and experimental groups. METHODOLOGY: Nine male Wistar rats were randomly divided into negative (n = 3), positive control (n = 3), and experimental groups (n = 3). Endogenous melatonin levels (pg/mL) were assessed, and an orthodontic force of 10 cN was applied to positive control and experimental groups using a ligature wire. The experimental group received a daily dose of 10 mg/kg melatonin via intraperitoneal injection. After eight weeks, blood samples and radiographs were collected, and mandible sections were prepared for histopathological and immunohistochemical evaluation. RESULTS: The radiographic evaluation shows minimal orthodontically induced tooth movement in comparison to the positive control group. In serological analysis, ALP was found to be increased in rats under the melatonin group. And, in the immunohistochemical evaluation, ALP was found to be increased in the melatonin group, whereas IL-6 was found to be decreased in the same (P = 0.027). CONCLUSIONS: The study elucidates that the administration of exogenous melatonin during orthodontic tooth movement in Wistar rats induces bone formation and inhibits resorption, eventually decelerating the process of orthodontic tooth movement. Our study emphasizes melatonin's dualistic role in stimulating bone production and suppressing resorption, offering potential therapeutic clinical implications in orthodontics.

Preventive and reparative effects of low-level laser therapy on orthodontically induced inflammatory root resorption-An animal study.

BACKGROUND: Orthodontically induced inflammatory root resorption (OIIRR) is one of the most important side effects of orthodontic treatment. Low-level laser therapy (LLLT) is a useful way to reduce the orthodontic treatment duration and may have some effect on preventing and repairing OIIRR. However, the specific effects of LLLT on OIIRR remain unknown. OBJECTIVE: Our research aimed to evaluate the Dentin Sialophosphoprotein (DSPP) expression level and root resorption volume during treatment and retention to explore the role of LLLT in preventing and repairing OIIRR. METHODS: Thirty-seven 6-week-old male Sprague-Dawley rats were selected to establish an OIIRR model; the rats were divided into Group B (blank), Group F (force), Group F(LLLT) (force and LLLT), Group F+R (force and retention) and Group F+R(LLLT) (force, retention and LLLT). The root resorption volume of the distal buccal root and mesial root in the maxillary left first molar was calculated by micro-CT, and the DSPP expression level on the compression side of the periodontal ligament was analysed by immunohistochemical staining. RESULTS: The resorption volume in Group F was greater than that in Group F(LLLT). For the mesial root, the volume in Group F was greater than that in Groups F+R and F+R(LLLT). For the distal buccal root, the volume in Groups F and F+R was greater than that in Group F+R(LLLT). The DSPP level in Group F(LLLT) was greater than that in Group F and there was no difference between Groups F+R and F+R(LLLT). CONCLUSIONS: LLLT has a certain preventive effect and a limited reparative effect on OIIRR in rats.

Inhibition of 12/15-lipoxygenase reduces orthodontically induced root resorption in rats.

OBJECTIVES: To investigate whether the inhibition of 12/15-lipoxygenase (12/15-LOX), one of the core enzymes of the arachidonic acid cascade, suppresses orthodontically induced root resorption (OIRR), and examine the involvement of the hyaline degeneration of periodontal ligament cells and odontoclast differentiation. MATERIALS AND METHODS: The left maxillary first molars of 10-week-old male Wistar rats were moved mesially for 14 days using a closed-coil spring (25 cN) inserted between the first molar and incisor. The rats were intraperitoneally administered with a 12/15-LOX specific inhibitor (ML-351; 0.05 mmol/kg) daily in the experimental group or vehicle (dimethyl sulfoxide) in the control group. Tooth movement was measured using microcomputed tomography on day 14. The appearance of OIRR, hyaline degeneration, osteoclasts, and odontoclasts was evaluated via histological analysis. Immunohistochemical staining for receptor-activated NF-kB ligand (RANKL) and osteoprotegerin was performed. RESULTS: OIRR observed on day 14 in the control group was strongly suppressed by ML-351 treatment. Hyaline degeneration observed on the compression side on day 3 and the appearance of osteoclasts and odontoclasts on days 3 and 14 were significantly suppressed by ML-351. RANKL expression on day 3 was significantly suppressed by ML-351. These key processes in OIRR were substantially suppressed by ML-351 treatment. CONCLUSIONS: Inhibition of 12/15-LOX reduced OIRR by suppressing hyaline degeneration and subsequent odontoclast differentiation.

Ubiquitin C-terminal hydrolase L1 activation in periodontal ligament cells mediates orthodontic tooth movement via the MAPK signaling pathway.

PURPOSE: Periodontal ligament cells (PDLCs) play a significant role in orthodontic force induced bone remodeling. However, the molecular mechanisms by which PDLCs respond to mechanical stimuli and influence osteoclastic activities remain unclear. This study aims to investigate the role of UCHL1, a key deubiquitinating enzyme involved in protein degradation and cellular responses, in force-treated PDLCs during orthodontic tooth movement (OTM). MATERIALS AND METHODS: In this study, we conducted in vivo and in vitro experiments using human PDLCs and a rat model of OTM. Mechanical stress was applied to PDLCs, and UCHL1 expression was analyzed through quantitative real-time polymerase chain reaction (qPCR), Western blot, and immunofluorescence staining. UCHL1 knockdown was achieved using siRNA, and its effects on osteoclast differentiation were assessed. The role of the MAPK/ERK pathway was investigated using the MEK-specific inhibitor U0126. An animal model of OTM was established, and the impact of UCHL1 inhibitor-LDN57444 on OTM and osteoclastic activity was evaluated through micro-CT analysis, histological staining, and immunohistochemistry. RESULTS: Mechanical force induced UCHL1 expression in PDLCs during OTM. UCHL1 knockdown downregulated the RANKL/OPG ratio in PDLCs, affecting osteoclast differentiation. LDN57444 inhibited OTM and osteoclastic activity. UCHL1 activation correlated with ERK1/2 phosphorylation in force-treated PDLCs. CONCLUSIONS: Mechanical force mediated UCHL1 activation in PDLCs promotes osteoclast differentiation via the ERK1/2 signaling pathway during OTM.

Influence of vitamin D in orthodontic tooth movement-a systematic review and meta-analysis of randomized controlled trials in humans.

BACKGROUND: Orchestration of tooth movement necessitates an equilibrium of bone synthesis and resorption. Vitamin D, through receptor-mediated actions, regulates the differentiation and maturation of osteoblasts and also induces osteoclastogenesis, maintaining this equilibrium. OBJECTIVE: To analyze the impact of vitamin D in orthodontic tooth movement (OTM). SEARCH METHOD: A comprehensive exploration of the existing literature was conducted by systematic search through seven e-databases. SELECTION CRITERIA: The criteria for inclusion were established using the PICO format: Orthodontic patients treated with fixed appliance (P), administered with vitamin D3 (I), collated with appropriate control groups (C), with tooth movement as the primary outcome and root resorption, anchorage loss, gingival crevicular fluid (GCF) volume, pain perception, and alveolar bone density as the secondary outcome (O). DATA COLLECTION AND ANALYSIS: After an extensive database search, 251 articles were obtained. Six articles were chosen following a stringent selection using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The critical appraisal of randomized control trials (RCTs) involved the meticulous application of the RoB 2 tool. The quantitative synthesis incorporated a subset of six articles only. RESULTS: In the meta-analysis investigating the influence of vitamin D on OTM, a notable disparity was evident between the vitamin D and control groups. Specifically, the standardized mean difference (SMD) stood at 1.43, accompanied by a 95% confidence interval (CI) ranging from 0.691 to 2.169 (P = .00154). For root resorption, the SMD was recorded at -0.51, with a 95% CI spanning from -3.051 to 2.031 (P = .11). CONCLUSIONS: The rate of tooth movement was enhanced by systemic and local administration of vitamin D. However, the inadequacy of available data is a hindrance in determining conclusively the impact of vitamin D on the extent of root resorption. The resolution of this quandary needs future human studies devoted toward investigating the influence of vitamin D in the realms of OTM and associated root resorption, thereby providing a definitive elucidation. REGISTRATION DETAILS: Prospero- CRD42023491783.

NFATc1 and RUNX2 Expression on Orthodontic Tooth Movement with Gradually Increasing Force.

Background: Orthodontic tooth movement occurs due to bone resorption and apposition on the pressure and tension side of the PDL. The transcription factors associated with osteoclast differentiation are NFATc1 while osteoblast differentiation is associated with RUNX2. The optimum force of orthodontic tooth movement can move the teeth to the desired position, without causing discomfort and tissue damage to the patient. Objective: This study aims to analyse the effect of gradually increasing force on orthodontic tooth movement (by evaluating the NFATc1 and RUNX2 expression) in rats. Methods: This research is an in vivo experimental study with a post-test control group design. Twenty-eight healthy male adult Wistar rats (Rattus novergicus) aged 4-5 months with body weights 200-250 g rats were divided into seven study groups. Treatment groups in this study are given the force (by applying a closed coil spring between the maxillary central incisor and the maxillary first molar) of 5 g, 5-10 g, 10 g, and 10-20 g with the duration of treatment in 14 and 28 days. After the treatment day was finished, the alveolar bone tissue was isolated and investigated by immunohistochemical methods. Results: Indicate a significant difference between the control and all treatment groups of NFATc1 (p=0.003; p=0.000; p:0.010; p=0.001; p=0.001; p=0.000) and RUNX2 with groups of 10 g/14 days, 10 g/28 days, 5 g/28 days, 10 g/14 days,10-20 g/28 days (p=0.001; p=0.000; p=0.000; p=0.017; p=0.014; p=0.000) values. Conclusion: Gradually increasing force affects orthodontic tooth movement by inducing bone resorption (high expression of NFATc1) in the pressure area and bone apposition (high expression of RUNX2) in the tension area. Applying heavy force by initially applying light force could inhibit hyalinization.

Reviewing the benefits and clinical outcomes of oral fibroblasts over mesenchymal stem cells for repairing periodontal defects during or after orthodontic tooth movement.

Orthodontic therapy applies forces to teeth, causing an inflammatory reaction in the periodontal ligament. This is repaired by remodeling of the periodontium, allowing tooth displacement. Although orthodontic therapy is mostly initiated during childhood and adolescence, the number of adults seeking this treatment is increasing as our society's esthetic awareness rises. However, adults may already have periodontal tissue abnormalities, rendering orthodontic treatment inefficient because a healthy periodontium is essential for success. Numerous risk factors have been linked to periodontal lesions, with orthodontic tooth movement possibly playing a minimal influence. Although such tissue damages are mostly of esthetic rather than functional concern for patients, restoration frequently requires invasive procedures. Autologous cells for the treatment of periodontal complications have grown in popularity as a less intrusive alternative. The present review analyzed the literature on the use of mesenchymal stem cells and oral tissue-derived fibroblasts for the healing of periodontal defects that may be related to orthodontic tooth movement. Furthermore, the advantages and challenges of the two cell types have been examined. Although the number of clinical studies is currently limited, our study demonstrates that oral fibroblasts have the potential to be the next emergent frontrunners for tissue engineering in the periodontium.

Effects of Vibration on Accelerating Orthodontic Tooth Movement in Clinical and In Vivo Studies: A Systematic Review.

This systematic review aims to assess the impact of high (>30 Hz) and low (≤30 Hz) frequency vibrations on orthodontic tooth movement (OTM). Several articles were collected through a systematic search in the databases MEDLINE and SCOPUS, following PRISMA methodology and using a PICO question. Relevant information on selected articles was extracted, and the quality of each study was assessed by the quality assessment tools EPHPP, ROBINS-1 and STAIR. Out of 350 articles, 30 were chosen. Low-frequency vibrations did not seem to accelerate OTM with aligners or fixed appliances, despite some positive outcomes in certain studies. Conversely, high-frequency vibrations were linked to increased aligner change, tooth movement, and space closure with fixed appliances. In vivo studies reported favourable results with high-frequency vibrations (60 Hz to 120 Hz), which stimulate bone biomarkers, facilitating alveolar bone remodelling. The results suggest that high-frequency vibration effectively speeds up orthodontic tooth movement, showing promise in both in vivo and clinical studies. Larger-scale research is needed to strengthen its potential in orthodontics.

Validation of reliable reference genes for qPCR of CD4+ T cells exposed to compressive strain.

For accurate interpretation of quantitative real-time PCR (qPCR) data, stable reference genes are essential for normalization of target genes. To date, there is no information on reliable housekeeping genes in CD4+ T cells in a three-dimensional (3D) matrix under pressure stimulation. This in vitro study describes for the first time a method for pressure stimulation of CD4+ T cells in a 3D matrix in the context of orthodontic tooth movement (OTM) and identifies a set of reliable reference genes. CD4+ T cells were isolated from murine spleen and activated with anti-CD3/-CD28 Dynabeads (Thermo Fisher, Langenselbold, Germany) on standard cell culture plates or in 3D scaffolds with or without compressive strain. Expression stability of nine potential reference genes was examined using four mathematical algorithms. Gene expression of Il2 was normalized to all potential reference genes to highlight the importance of correct normalization. Cell proliferation and the expression of the surface markers CD25 and CD69 were also determined. The 3D matrix did not inhibit proliferation after immunological activation of T cells and embedded the cells sufficiently to expose them to pressure load. Expression of ubiquitin C (Ubc) and hypoxanthine phosphoribosyltransferase (Hprt) was the most stable under all conditions tested. A combination of these two genes was suitable for normalization of qPCR data. Normalization of Il2 gene expression showed highly variable results depending on the reference gene used. Pressure reduced cell proliferation and the number of CD69-positive T cells. This study provides a basis for performing valid and reliable qPCR experiments with CD4+ T cells cultured in 3D scaffolds and exposed to compressive forces simulating OTM.

TNF reduces osteogenic cell fate in PDL cells at transcriptional and functional levels without alteration of periodontal proliferative capacity.

AIMS: To investigate the effect of tumor necrosis factor (TNF) on the growth of human periodontal ligament (PDL) cells, their osteogenic differentiation and modulation of their matrix secretion in vitro. METHODS: The influence of 10 ng/ml TNF on proliferation and metabolic activity of PDL cells was analyzed by cell counting (DAPI [4',6-diamidino-2-phenylindole] staining) and the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. In addition, cells were cultured under control conditions and osteogenic conditions (media containing 10 mM ß-glycerophosphate). Quantitative expression analysis of genes encoding the osteogenic markers alkaline phosphatase (ALP), collagen type I alpha 1 chain (COL1A1), osteoprotegerin (OPG), and osteopontin (OPN) was performed after 7 and 14 days of cultivation. Calcium deposits were stained with alizarin red. RESULTS: Our studies showed that 10 ng/ml TNF did not affect the survival and metabolic activity of PDL cells. Quantitative expression analysis revealed that long-term cultures with TNF impaired osteogenic cell fate at early and late developmental stages. Furthermore, TNF significantly reduced matrix secretion in PDL cells. CONCLUSION: The present data confirm TNF as a regulatory factor of proinflammatory remodeling that influences the differentiation behavior but not the metabolism and cell proliferation of the periodontium. Therefore, TNF represents an interesting target for the regulation of orthodontic remodeling processes in the periodontium.

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.

Enhancement of Orthodontic Tooth Movement by Local Administration of Biofunctional Molecules: A Comprehensive Systematic Review.

Enhancement of orthodontic tooth movement (OTM) through local administration of biofunctional molecules has become increasingly significant, particularly for adult patients seeking esthetic and functional improvements. This comprehensive systematic review analyzes the efficacy of various biofunctional molecules in modulating OTM, focusing on the method of administration and its feasibility, especially considering the potential for topical application. A search across multiple databases yielded 36 original articles of experimental human and animal OTM models, which examined biofunctional molecules capable of interfering with the biochemical reactions that cause tooth movement during orthodontic therapy, accelerating the OTM rate through their influence on bone metabolism (Calcitriol, Prostaglandins, Recombinant human Relaxin, RANKL and RANKL expression plasmid, growth factors, PTH, osteocalcin, vitamin C and E, biocompatible reduced graphene oxide, exogenous thyroxine, sclerostin protein, a specific EP4 agonist (ONO-AE1-329), carrageenan, and herbal extracts). The results indicated a variable efficacy in accelerating OTM, with Calcitriol, Prostaglandins (PGE1 and PGE2), RANKL, growth factors, and PTH, among others, showing promising outcomes. PGE1, PGE2, and Calcitriol experiments had statistically significant outcomes in both human and animal studies and, while other molecules underwent only animal testing, they could be validated in the future for human use. Notably, only one of the animal studies explored topical administration, which also suggests a future research direction. This review concluded that while certain biofunctional molecules demonstrated potential for OTM enhancement, the evidence is not definitive. The development of suitable topical formulations for human use could offer a patient-friendly alternative to injections, emphasizing comfort and cost-effectiveness. Future research should focus on overcoming current methodological limitations and advancing translational research to confirm these biomolecules' efficacy and safety in clinical orthodontic practice.

KAT6A/YAP/TEAD4 pathway modulates osteoclastogenesis by regulating the RANKL/OPG ratio on the compression side during orthodontic tooth movement.

BACKGROUND: Orthodontic tooth movement (OTM) is a dynamic equilibrium of bone remodeling, involving the osteogenesis of new bone and the osteoclastogenesis of old bone, which is mediated by mechanical force. Periodontal ligament stem cells (PDLCSs) in the periodontal ligament (PDL) space can transmit mechanical signals and regulate osteoclastogenesis during OTM. KAT6A is a histone acetyltransferase that plays a part in the differentiation of stem cells. However, whether KAT6A is involved in the regulation of osteoclastogenesis by PDLSCs remains unclear. RESULTS: In this study, we used the force-induced OTM model and observed that KAT6A was increased on the compression side of PDL during OTM, and also increased in PDLSCs under compression force in vitro. Repression of KAT6A by WM1119, a KAT6A inhibitor, markedly decreased the distance of OTM. Knockdown of KAT6A in PDLSCs decreased the RANKL/OPG ratio and osteoclastogenesis of THP-1. Mechanistically, KAT6A promoted osteoclastogenesis by binding and acetylating YAP, simultaneously regulating the YAP/TEAD axis and increasing the RANKL/OPG ratio in PDLSCs. TED-347, a YAP-TEAD4 interaction inhibitor, partly attenuated the elevation of the RANKL/OPG ratio induced by mechanical force. CONCLUSION: Our study showed that the PDLSCs modulated osteoclastogenesis and increased the RANKL/OPG ratio under mechanical force through the KAT6A/YAP/TEAD4 pathway. KAT6A might be a novel target to accelerate OTM.

Periodontal Ligament Cell Apoptosis Activates Lepr+ Osteoprogenitors in Orthodontics.

Alveolar bone (AB) remodeling, including formation and absorption, is the foundation of orthodontic tooth movement (OTM). However, the sources and mechanisms underlying new bone formation remain unclear. Therefore, we aimed to understand the potential mechanism of bone formation during OTM, focusing on the leptin receptor+ (Lepr+) osteogenitors and periodontal ligament cells (PDLCs). We demonstrated that Lepr+ cells activated by force-induced PDLC apoptosis served as distinct osteoprogenitors during orthodontic bone regeneration. We investigated bone formation both in vivo and in vitro. Single-cell RNA sequencing analysis and lineage tracing demonstrated that Lepr represents a subcluster of stem cells that are activated and differentiate into osteoblasts during OTM. Targeted ablation of Lepr+ cells in a mouse model disrupted orthodontic force-guided bone regeneration. Furthermore, apoptosis and sequential fluorescent labeling assays revealed that the apoptosis of PDLCs preceded new bone deposition. We found that PDL stem cell-derived apoptotic vesicles activated Lepr+ cells in vitro. Following apoptosis inhibition, orthodontic force-activated osteoprogenitors and osteogenesis were significantly downregulated. Notably, we found that bone formation occurred on the compression side during OTM; this has been first reported here. To conclude, we found a potential mechanism of bone formation during OTM that may provide new insights into AB regeneration.

Biomodulation effects induced by ultrasound stimulation in periodontal cells implicated in orthodontic tooth movement: A systematic review.

Accelerating orthodontic tooth movement (OTM) is increasingly important for shorter treatment times, which reduces periodontal risks, root resorption and dental caries. Techniques to accelerate OTM focus on stimulating bone remodelling by enhancing osteoclast and osteoblast activity and include both surgical and non-surgical methods. The therapeutic potential of ultrasounds is highly recognized among many medical areas and has shown promising results in modulating bone remodelling and inflammation phenomena. This systematic review aims to collect and analyse the current scientific in vitro and ex vivo evidence on ultrasound stimulation (US) bioeffects in cells implicated in tooth movement. This review was conducted according to PRISMA 2020 guidelines. A bibliographic search was carried out in the PubMed, Scopus and Web of Science databases. Sixteen articles were selected and included in this review. The revised studies suggest that US of 1.0 and 1.5 MHz, delivered at 30 mW/cm2, 10 to 30 min daily over three to 14 days seems to be effective in promoting osteoclastogenic activity, while US of 1.5 MHz, 30 to 90 mW/cm2, in 5- to 20-min sessions delivered daily for 5 to 14 days exhibits the potential to stimulate osteogenic activity and differentiation. Previous research yielded varied evidence of the effectiveness of US in orthodontics. Future animal studies should employ the recommended US parameters and investigate how distinct protocols can differentially impact tissue remodelling pathways. The knowledge arising from this review will ultimately potentiate the application of US to accelerate OTM in the clinical setting.