Proinflammatory and anti-inflammatory cytokines in modulating bone remodeling during orthodontic tooth movement

Abstract

Objectives

This systematic review and meta-analysis sought to assess the influence of proinflammatory (interleukin [IL]-1β, IL-6, tumor necrosis factor α) and anti-inflammatory (IL-10, IL-4, IL-1RA) cytokines on bone remodeling during orthodontic tooth movement. The aim was to clarify their dynamics over time and space and evaluate their potential as clinical biomarkers.

Search Strategy

The review adhered to the Preferred Reporting Items for Systematic reviews and Meta-analyses 2020 guidelines. A structured population, intervention, comparator, outcome framework directed the search. Medical Subject Heading terms alongside free-text key words were used in combination with Boolean operators across various databases (PubMed, Embase, Scopus, Cochrane Library, Web of Science) from 2000 through 2024. The reference lists of the included studies were examined manually to ensure thoroughness.

Citation Sources

Searching electronic databases and conducting manual reference checks resulted in an initial collection of 85 studies of which 14 met the criteria for inclusion.

Study Selection Criteria

The studies eligible for inclusion measured cytokine levels (IL-1β, IL-10, IL-1RA, IL-4) in gingival crevicular fluid, saliva, or serum throughout orthodontic treatment. No age, sex, or appliance type restrictions were imposed on the participants. Both observational and interventional human studies were considered.

Data Elements Included

Data extraction included details such as authorship, methodology, biological fluid examined, cytokines investigated, detection technique (enzymed-linked immunosorbant assay, multiplex assay, polymerase chain reaction), sample size, and key outcomes. Quality assessment was conducted using the Newcastle-Ottawa Scale.

Overall Conclusions

Proinflammatory cytokines showed early peaks after the application of orthodontic force, triggering bone resorption at compression sites. In contrast, anti-inflammatory cytokines appeared later, facilitating repair and bone deposition at tension sites. IL-1β levels were positively correlated with the rate of tooth movement, while lower levels of IL-1RA were associated with quicker distal displacement. Although the pooled results from the meta-analysis did not show statistically significant differences, consistent trends supported the regulatory role of cytokines in orthodontic tooth movement. Future investigations should focus on larger, multicenter studies using standardized protocols to confirm the reliability of cytokines as biomarkers for precise orthodontic treatments.

Graphical abstract

Introduction

In dentistry, orthodontics deals with the surveillance, guidance, and modification of developing and mature dentofacial structures. Acute inflammation, bone resorption, and bone creation are the initial reactions to orthodontic stress. Orthodontic tooth movement (OTM) and physiological tooth movement are 2 categories of tooth movement.¹ OTM is a biomechanical process that results in a coordinated process of bone remodeling by causing local hypoxia and stimulating an aseptic inflammatory response in the periodontal tissue by exerting pressure on the teeth.² The microtrauma caused by orthodontic movement to the periodontal ligament (PDL) is linked to a localized periodontal inflammatory cycle.³ Activation, resorption, reversal, and reconstruction of new bones are the 4 phases into which the progression of tooth movement can be divided.¹

The dental and paradental tissues can be altered by the use of orthodontic force.^1,2 The deflecting, or bending, of the alveolar bone and the remodeling of the periodontal tissues, which involve the gingiva, alveolar bone, dental pulp, and PDL, are 2 interrelated events that influence OTM.² According to the pressure-tension theory linked to OTM, mesenchymal stem cells will be activated by the application of physiological force, which includes PDL compressional and tensional alterations.³ Force-exposed PDL progenitor cells will develop into tension-associated osteoblasts and compression-associated osteoclasts, which result in bone apposition and resorption, respectively.⁴ Within hours of the orthodontic force being applied, the multipotent mesenchymal stem cells start to differentiate.²

Proteins such as growth factors, cytokines, chemokines, and extracellular matrix proteins interact intricately to cause periodontal tissue remodeling in relation to orthodontic force.^5,6 Cytokines are proteins with lower molecular weights (< 25 kDa) that respond to local signals such as stress and play a role in the turnover of bones and remodeling. Leukocyte-secreted cytokines can interact directly with osteoblasts or indirectly through related cells such as fibroblasts, lymphocytes, monocytes, and macrophages, which produce cytokines or other growth factors.⁷ From the beginning of inflammation to its resolution, cytokines and eicosanoids play a role.

Cytokines that stimulate inflammation, such as interleukin (IL)-1β, IL-2, IL-5, IL-8, IL-6, tumor necrosis factor α (TNF-α), interferon-γ, and granulocyte-macrophage colony-stimulating factor, cause blood vessels to widen and white blood cells to infiltrate tissues. In contrast, anti-inflammatory cytokines such as IL-4 and IL-10 help resolve the inflammatory process.³ Cytokines in gingival crevicular fluid (GCF) are being extensively examined as quantitative biochemical indicators of periodontal inflammation, but researchers are now increasingly concentrating on recognizing their function as mediators of orthodontic tooth motion owing to their role in bone and tissue remodeling.⁷

IL-4, which was previously identified as a B-cell growth factor, is a potent macrophage inhibitor.⁷ The lack of IL-4 in certain locations of infected periodontal tissues is connected to the progress and activity of the disease.⁷ T-helper–type 2 cells generate IL-4, which strongly suppresses receptor activator of nuclear factor κB ligand–induced osteoclastogenic activity. When injected locally, IL-4 inhibited tooth mobility and root resorption by reducing the underlying osteoclastogenesis and odontoclastogenesis. These data suggest that IL-4 has therapeutic potential in controlling OTM and reducing root resorption during orthodontic treatment.⁸ As a result, the lack of IL-4 may worsen osteoclastogenesis when orthodontic stress is given to teeth with periodontitis.⁸

IL-10 typically enhances tissue inhibitors of metalloproteinases and suppresses matrix metalloproteinase activity, potentially contributing to the preservation of tissue integrity and extracellular matrix deposition. Researchers observed positive correlations between IL-10, collagen type I, and tissue inhibitors of metalloproteinase–1 levels, supporting IL-10’s possible anabolic role. Elevated IL-10 expression could be linked to reduced osteoclast function and increased osteoblast activity, which are characteristic of the T side.⁴ Orthodontic forces can suppress IL-10 expression.⁶ IL-1β is a more potent promoter of bone resorption and inhibitor of bone formation.⁹ IL-1β, a powerful cytokine primarily produced by activated monocytes, increases substantially during inflammation and plays a role in initiating bone resorption.⁷ IL-1 and its competitive inhibitor, IL-1 receptor antagonist (IL-1RA), represent 1 pair of proinflammatory cytokines. The elevated mean activity index values and comparatively reduced average IL-1RA concentrations in GCF at test sites correlate with enhanced relative bone resorption and accelerated tooth movement. Diminished average IL-1RA levels in GCF at experimental locations are linked to quicker distal tooth displacement.¹⁰ The advent of precision medicine necessitates elucidation of individual mechanisms, including messenger RNA expression and cytokine secretion, during OTM treatment.¹¹

Although research has delved into the biomechanics of OTM, the complex interplay between proinflammatory and anti-inflammatory cytokines in bone remodeling is not yet completely understood. Important cytokines such as IL-1β, IL-10, IL-1RA, and IL-4 are crucial in managing inflammation, but their collective influence on the rate and quality of tooth movement is still uncertain. Our study aims to address this gap by investigating the interactions of these cytokines and their potential role in enhancing orthodontic treatment for improved efficiency and patient outcomes. We aim to answer the question “What is the role of proinflammatory cytokines and anti-inflammatory cytokines in OTM?”

Methods

Our systematic review and meta-analysis used the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 standards.¹² Before beginning the search, the population, intervention, comparator, outcome (PICO) structure was determined (Figure 1).

Figure 1.

Preferred Reporting Items for Systematic reviews and Meta-Analyses flowchart.

PICO framework

The PICO framework for our article was as

• •Population: patients with malocclusion
• •Intervention: orthodontic treatment
• •Comparator: patients with and without malocclusion
• •Outcome: cytokine measurements of IL-1β, IL-10, IL-1RA, and IL-4

Inclusion criteria

Our systematic review and meta-analysis include studies that measured cytokine levels (IL-1β, IL-10, IL-1RA, IL-4) in GCF, saliva, or serum after orthodontic therapy. There were no limitations on age, sex, or type of orthodontic treatment.

Research methodology and data collection

We used the PICO framework to develop a search strategy. Medical subject heading terms, controlled vocabulary, and free text were used for performing detailed searches in PubMed, Scopus, and Web of Science databases. Lists of references of those included were reviewed as well to detect further pertinent articles. A literature evaluation was conducted of articles published from 2000 through 2024 using a variety of electronic databases, including PubMed, Embase, the Cochrane Library, Scopus, and Web of Science. Our aim was to identify studies focusing on the predictive role of cytokine ratios (IL-1β, IL-10, IL-1RA, IL-4) in orthodontic treatment outcomes. Our search strategy incorporated medical subject heading terms and key words, combined with Boolean operators for comprehensive coverage. Key search components included cytokines and interleukins (“Cytokines” OR “Cytokine Ratios” OR “IL-1β” OR “IL-10” OR “IL-4”), orthodontic treatment (Orthodontics” OR “Orthodontic Tooth Movement” OR “Root Resorption”), biomarkers in GCF (“Gingival Crevicular Fluid” OR “GCF” AND “Biological Markers”), treatment outcomes (“Predictive Value of Tests” OR “Treatment Outcome”). To ensure that all studies were included, no limits on their publication date were applied. Manually examining the reference list from the included research was done to locate additional relevant papers.

Study selection process

The search results were transferred into Zotero (Corporation for Digital Scholarship), reference management software that automatically removes duplicates. Two independent reviewers (N.V., R.R.) examined the titles and abstracts of the retrieved documents. After the preliminary screening, the entire texts of possibly eligible records were assessed by the same reviewers using established eligibility criteria. A third reviewer (K.K.) handled any differences over document selection.

Data extraction and quality assessment

Two reviewers extracted past data to develop a standardized form. The completed data extraction sheet extracted information from eligible records about the authors, methods, results, future directions, and conclusions.

Quality assessment

The quality of the included nonrandomized studies was evaluated using the Newcastle-Ottawa Scale (NOS). Each study was assessed using a star system, with individual questions receiving 1 or 2 stars. On the basis of the total stars received, studies were classified as good, satisfactory, or unsatisfactory.

Summary synthesis

To identify any potential limitations in the included studies that could affect the reliability of the results, we conducted an evaluation of the risk of bias in our systematic review. The main areas of concern are highlighted in the summary of bias risk. We use RevMan (Cochrane) software to create a forest plot, which visually represents the effect sizes and CIs from multiple studies. In addition, we used a funnel plot to assess publication bias by looking for trends that may indicate small-study effects or selective reporting. Together, these analyses ensure that the results are clear, reliable, and trustworthy.

Risk of bias

Our comprehensive review evaluated the risk of bias across various studies and presented the findings in a graphical format (Figure 2). Most investigations showed solid methodological approaches and reliable outcome reporting, with minimal risk of selective reporting bias. However, some studies lacked detailed methodological descriptions, highlighting the need for greater transparency. A limitation was the small sample size in several studies, which decreased statistical power and the applicability of the findings. In addition, certain studies used inadequate statistical methods, raising concerns about the validity of the conclusions. The low incidence of attrition bias and other forms of bias improved the overall credibility of the reviews. To enhance the quality of future research, it is essential to follow established statistical procedures, use appropriately sized samples, and clearly outline study designs and strategies for handling missing data. Addressing these issues can help researchers raise the standard of evidence and the reliability of systematic reviews.

Figure 2.

Risk of bias.

Risk-of-bias summary

A review of the research reveals minimal bias in key areas such as methodological selection, study design, and selective reporting, suggesting that results in these domains are generally solid and trustworthy. However, a concern is the sample size; many studies in this field have been categorized as high risk of bias, which may lead to lower statistical power and less generalizable results. In addition, statistical analyses vary widely, with some studies using suboptimal techniques that result in ambiguous or elevated hazard ratios. Issues such as attrition bias and other potential biases are typically minimal across the research, enhancing the overall credibility of the findings. Future research should focus on increasing sample sizes, providing detailed and comprehensive descriptions of study procedures, and adhering to strict statistical guidelines to improve the validity and reliability of the findings, ultimately raising the quality of evidence in systematic reviews (Figure 3).

Figure 3.

Risk-of-bias summary.

Results

Search results

In our investigation, we initially discovered 87 records through database searches, after eliminating 2 duplicates and 1 record for other reasons. Of these, 11 were excluded during the screening phase and 4 could not be obtained, resulting in 72 articles evaluated for eligibility. After thorough assessment, 58 studies were disregarded, and 14 studies and 2 reports met the criteria for final inclusion and data extraction, as shown in Figure 1 and Table 1.

Table 1.

Summary of search results for included studies.

Study	Methodology	Results	Future Research	Statistics	Conclusions
Iwasaki et al,2 2001	Controlled force magnitudes and area of force application Measured cytokine concentrations in GCF∗	The velocity of tooth movement correlates with cytokine concentrations Stronger correlation from distal than mesial retracted teeth	Need further modifications to the activity index that will reflect the effects of concentrations of several other factors involved in bony remodeling, rather than just IL†-1β and IL-1RA‡	The strength of correlation between the velocity of the distal canine movement and the activity index was measured with a Pearson product-moment correlation coefficient	Tooth movement velocity correlates with cytokine concentrations in GCF Individual differences in cytokine production affect canine retraction speed
Garlet et al,3 2007	Real-time polymerase chain reaction for messenger RNA expression analysis Statistical analysis using ANOVA§ and linear regression	Higher cytokine expression in compression and tension sides compared with controls Differential expression patterns of cytokines in compression and tension sides	Role of proinflammatory mediators in tissue remodeling Role of anti-inflammatory mediators in OTM¶	ANOVA and Bonferroni tests were used for statistical analysis P < .05 is considered statistically significant	Differential cytokine expression in periodontal ligament during tooth movement was observed Higher TNF#-α in compression; higher IL-10 in the tension side
Ren et al,6 2007	GCF sampling at various times postforce application Analysis of PICs∗∗ using a multiplex technique	PICs elevated significantly during early tooth movement stages IL-1β, IL-6, and TNF-α were significant at 24 h	To focus on more frequent times in the early stage of tooth movement to define an exact sequence of the appearance of the PICs, and combine measurements at the translation and transcription levels to discover the control mechanism of cytokine levels	Mann-Whitney tests were used when comparisons were made between 2 groups, and Kruskal-Wallis tests were used when comparisons were made between > 2 groups	Proinflammatory cytokines are elevated during early tooth movement stages Different cytokines peak at various times
Giannopoulou et al, 200813	Clinical examination of plaque, probing depth, and bleeding GCF collection using Durapore (3M) strips and ELISA†† analysis	Higher IL-1β and IL-8 in the orthodontic group No significant difference in IL-4 levels	Investigate cytokine variations during different puberty stages Explore the long-term effects of orthodontic treatment on periodontal health	Statistical analyses included t tests and χ2 tests Mixed model analysis for cytokine logarithms was used	Fixed orthodontic appliances increase IL-1β and IL-8 expression Puberty may also influence cytokine expression levels
Iwasaki et al,5 2009	Segmental mechanics for distal translation of maxillary canines Collection and analysis of GCF samples via ELISA kits	Faster tooth movement linked to IL-1 gene polymorphisms Increased activity index and decreased IL-1RA are associated with speed	Larger samples and gene interactions in orthodontics Investigate person-specific characteristics affecting tooth movement variability	Average speeds of tooth movement ranged from 0.028 through 0.067 mm/d Significant factors affecting speed had P = .0391, R2 = 0.691	Faster tooth movement is linked to IL-1β allele 2 presence Higher stresses and growth evidence enhance tooth movement speed
Grant et al,1 2013	GCF samples were collected using periopaper strips Multiplex assays measured cytokines and biomarkers in GCF	Significant increases in cytokines and biomarkers during orthodontic treatment Correlation between GCF volume and tooth movement speed observed	Optimizing orthodontic forces using GCF biomarker analysis Investigating inflammatory responses during OTM	Paired nonparametric statistics (Kruskal-Wallis) were used for analysis Correlations were analyzed by Spearman rank sum analysis	Increased IL-1β, IL-8, and TNF-α at tension sites postforce application matrix metallopeptidase 9 was elevated at compression sites from 4 through to 7 d
Leethanakul et al, 201614	Elastic chain for canine retraction force-loading technique Prestretched chains to activate the force degradation effect	IL-1β levels are sensitive to inflammation types monitored Healthy periodontal status was maintained in study participants	A long-term clinical study with a larger sample size is warranted	The Wilcoxon signed rank test was used to compare the levels of IL-1β and the amount of tooth movement between the experimental and control sites and between the compression and tension sites of each group	IL-1β levels sensitive to inflammation types are monitored carefully Elastic chains are preferred for routine canine retraction
Vujačić et al,4 2017	ELISA assays were used for cytokine levels GCF sampled at specific times	IL-1β and IL-6 levels peak at 24 and 168 h Children show higher IL-6 levels and faster tooth movement	Investigate cytokine levels in different orthodontic treatments Explore age-related differences in inflammatory responses further	Mann-Whitney tests were used for statistical analysis P < .05 was considered significant	GCF IL-1β and IL-6 levels increase during the initial OTM phase IL-6 levels rise faster in children than in young adults
de Oliveira Chami et al,9 2018	Collected GCF samples at specific times Quantified cytokine levels using Luminex’s multianalysis technology	Cytokine levels remained constant after 21 d macrophage inflammatory protein-1β decreased from 24 h through 21 d	Investigate long-term cytokine behavior during orthodontic treatment Explore additional cytokine roles in tissue remodeling	Nonparametric tests were used for cytokine comparisons 11 patients with a mean age of 23.6 y	Cytokines play a role in tissue remodeling macrophage inflammatory protein-1β levels decreased after 21 d
Afacan et al,7 2019	Longitudinal, split-mouth, randomized controlled trial design GCF samples analyzed by multiplexed immunoassay	Both forces upregulated TNF-α and IL-1RA at 28 d Higher force (150 g) reduced IL-8 and MCP-1‡‡ at 24 h	Investigate the effects of different orthodontic forces on GCF analytes Explore long-term impacts of force magnitude on periodontal health	15 people participated in the study Significant cytokine changes were observed at 28 d	Higher force did not increase canine movement or GCF production Cytokine levels were differentially regulated by force magnitude and duration
Jayaprakash et al,8 2019	Collected GCF from participants Used ELISA assays to determine cytokine levels	Elevated cytokine levels in GCF during OTM Control groups showed no significant cytokine changes	Increase sample size Investigate cytokine levels in different orthodontic treatments and at different time intervals	10 participants with a mean age of 15.6 y Significant cytokine level differences at 24 h postactivation	Cytokine changes in GCF relate to OTM Elevated cytokines indicate a role in bone remodeling processes
Baeshen,11 2021	Flow cytometry for cytokine and cell marker analysis. ELISA for quantifying defensin protein levels in saliva	Higher IL-1β, MCP-1, IL-17A, and IL-6 in lingual samples Lower defensin levels in conventional lingual patients	Observing regulatory molecules for orthodontic treatment advancements Developing innovative methods for orthodontic equipment improvement	40 saliva samples analyzed: 20 lingual, 20 labial Significant differences in MCP-1, IL-17A, and IL-6 levels	Significant cytokine differences in saliva between appliance types Higher IL-1β, MCP-1, IL-17A, and IL-6 in lingual patients
Camarena Fonseca et al, 202215	Descriptive longitudinal study with 10 miniscrews cytometric bead array for cytokine measurement	Highest cytokine levels at 24 h postinsertion No significant increase from loading compared with insertion	Evaluate the regulatory factors of inflammatory biomarkers in signaling pathways Increase sample size to assess miniscrew failure associations	ANOVA used for statistical significance comparison Significant differences were found for IL-1β and IL-8	Loading did not increase cytokine levels beyond insertion effects The highest cytokine levels were observed 24 h postinsertion
Ratanasereeprasert et al,10 2024	GCF collection and tooth extraction after force application RNA exome sequencing and multiplex immunoassay analysis	Cytokine levels varied among patients during orthodontic treatment Specific gene expressions changed at different times	Investigate genetic factors influencing OTM in humans Explore cytokine release variations among different patients	To identify the differentially expressed genes among all 3 participants, a statistical significance indicated by log 2-fold change was used	Cytokine changes in GCF relate to OTM Elevated cytokines indicate a role in bone remodeling processes

^∗GCF: Gingival crevicular fluid.

^†IL: Interleukin.

^‡IL-1RA: Interleukin-1 receptor antagonist.

^§ANOVA: Analysis of variance.

^¶OTM: Orthodontic tooth movement.

^#TNF-α: Tumor necrosis factor α.

^∗∗PICs: Proinflammatory cytokines.

^††ELISA: Enzyme-linked immunosorbent assay.

^‡‡MCP-1: Monocyte chemoattractant protein-1.

Quality assessment

We evaluated the quality of the included studies using the NOS, which rates studies as good (7-9 stars), satisfactory (5-6 stars), or unsatisfactory (0-4 stars). Seven studies (78%) achieved a good rating, reflecting strong methodological rigor, especially in areas like sample selection, comparability, and outcome assessment. For instance, studies examining cytokine profiles in GCF and the effects of vibratory stimulation each scored 8 of 9 stars. The remaining 3 studies (22%) were rated as satisfactory, indicating moderate reliability with some methodological limitations, particularly in comparability. Examples include research on salivary proinflammatory cytokines and IL-1 gene polymorphisms. None of the studies fell into the unsatisfactory category, indicating an overall high-quality evidence base.

However, none of the included studies conducted sample size estimations, which could affect the statistical confidence of their findings. In addition, there was variability in study designs. To enhance reliability, future studies should focus on proper case selection and matching controls. Moreover, to better understand the role of cytokines and their relationship with anti-inflammatory agents, researchers should use standardized methodologies and larger sample sizes to improve statistical power and generalizability.

Characteristics of included studies

Table 1 summarizes the included articles, which were conducted in various countries, primarily evaluating GCF to analyze cytokine levels during OTM. Commonly used quantification methods include multiplex assays, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Sample sizes ranged from 10 through 66 participants. For statistical analysis, nonparametric tests such as Kruskal-Wallis, Mann-Whitney, analysis of variance, and Spearman rank sum test were used.

Most of the included studies showed a relationship between cytokine levels and the rate of tooth movement. Grant et al¹ reported elevated IL-1β, IL-8, and TNF-α levels in tension zones after force application. Similarly, Iwasaki et al² linked cytokine concentrations with canine retraction rates, and Garlet et al³ identified distinct cytokine patterns at compression and tension sites, underlining their role in bone remodeling. Although most studies had short follow-up periods (24 hours through several weeks), few, such as Vujačić et al,⁴ addressed long-term cytokine responses, highlighting the need for extended observations.

The pooled results from the meta-analysis are depicted in the forest plot (Figure 4). The overall impact estimate and standardized mean difference (SMD) with CI values are visually summarized. The diamond representing the pooled estimate lies close to 0, indicating no statistically significant difference between experimental and control groups. The narrow CI range suggests a relatively precise estimate. However, some studies display heterogeneity, as reflected by nonoverlapping CI values, potentially because of variations in methodology or study populations. This highlights the importance of large sample sizes and methodological consistency in future studies to draw stronger conclusions.

Figure 4.

Forest plot showing the pooled standard mean difference with 95% CIs for experimental vs control groups, analyzed using a fixed-effects inverse variance model.

Cytokines showed distinct spatial and temporal expression patterns. Proinflammatory mediators such as IL-1β, IL-6, TNF-α, and martix metalloproteinase–9 initiate bone resorption at compression sites. Grant et al¹ and Iwasaki et al^2,5 found elevated IL-1β and TNF-α at force-applied regions. Ren et al⁶ and Afacan et al⁷ showed a peak in IL-1β and IL-6 within 24 hours, reinforcing their early role in OTM. IL-1β levels were positively correlated with the speed of canine movement.⁷ In contrast, anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β facilitate tissue repair and bone deposition at tension sites. Garlet et al³ observed IL-10 predominance on the tension side, contrasting with TNF-α dominance in compression zones. Vujačić et al⁴ and Jayaprakash et al⁸ showed the delayed rise of anti-inflammatory cytokines, essential for resolving inflammation and remodeling tissues after initial force application.

To assess publication bias, a funnel plot was generated (Figure 5). Visual inspection revealed approximate symmetry, suggesting a low risk of publication bias among the included studies. However, slight asymmetry in a few cases may hint at small-study effects or methodological variability, reinforcing the need for standardized protocols in cytokine sampling and quantification.

Figure 5.

Funnel plot.

Discussion

Our comprehensive analysis examines the effect of cytokines on the movements of OTM. The research under consideration shows the crucial role that cytokines play in the remodeling of bones during orthodontic therapy by exhibiting substantial patterns in inflammation and anti-inflammation processes. During the initial phases of OTM, proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 are frequently elevated in GCF. This lends credence to the notion that the production of cytokines is a physiological reaction to orthodontic stresses, triggering osteoclast and osteoblast activity to start bone remodeling. For instance, during the first 24 hours of applying force, Iwasaki et al² and Ren et al⁶ showed increases. The variation in cytokine expression between the tooth’s tension and compression sides was a similar finding across articles.^2,6 Garlet et al³ found that the tension side had more IL-10 and the compression side had more TNF-α, indicating different molecular pathways for bone growth and resorption. This was further corroborated by Grant et al,¹ who connected the rate of tooth movement with cytokine levels. However, cytokine expression differed from person to person and by treatment method. Cytokine profiles were affected by variables such as patient age, genetic variations, and the force applied.

Vujačić et al⁴ discovered that children’s IL-6 levels were higher than those in adults, indicating age-related variations in inflammatory responses,⁴ whereas Iwasaki et al⁵ emphasized the impact of IL-1 gene polymorphisms on tooth movement speed. These revelations highlight the necessity of customized orthodontic treatment plans. Methodologically, the research measured cytokine levels using a variety of analytical approaches, such as RNA exome sequencing, multiplex assays, and enzyme-linked immunosorbent assays (Table 2). Although these techniques yield useful data, small sample sizes can occasionally restrict the dependability of the results. For example, de Oliveira Chami et al⁹ had only 11 patients, which raises questions regarding statistical power. Larger, multicenter studies should be conducted in the future to address this and produce more reliable findings.

Table 2.

Biological fluid–dependent variations in IL^∗-1β, IL-10, IL-1RA,^† and IL-4 during orthodontic treatment.

Cytokine	Study	Biological Fluid	Key Observations or Conclusions
IL-1β	Grant et al,1 2013	GCF‡	Increased at tension sites postforce; correlates with tooth movement speed
IL-1β	Iwasaki et al,2 2001	GCF	Correlates with tooth movement velocity; individual variation influences cytokine expression
IL-1β	Ren et al,6 2007	GCF	Peaks within 24 h postforce; early-phase mediator in tooth movement
IL-1β	Camarena Fonseca et al, 202215	GCF	Highest levels 24-h postminiscrew insertion; not increased by subsequent loading
IL-1β	Baeshen,11 2021	Saliva	Elevated in lingual appliance users; reflects appliance-driven systemic inflammation
IL-1β	Giannopoulou et al, 200813	GCF	Elevated in the orthodontic group; IL-4 unchanged; puberty may influence cytokine levels
IL-1β	Vujačić et al,4 2017	GCF	Peaks at 24 and 168 h; higher IL-6 in children indicates a stronger inflammatory response
IL-1β	Iwasaki et al,5 2009	GCF	Gene polymorphisms linked to faster movement and altered IL-1β and IL-1RA balance
IL-1β	Leethanakul et al, 201614	GCF	Sensitive to compression and tension sites; useful for site-specific monitoring
IL-1β	Jayaprakash et al,8 (2019)	GCF	Elevated postactivation; supports the role in bone remodeling
IL-1β	Ratanasereeprasert et al,10 2024	GCF	Patient-specific expression patterns; supports a personalized approach to orthodontics
IL-10	Garlet et al,3 2007	GCF	Higher on the tension side; counteracts proinflammatory cytokines such as tumor necrosis factor α during orthodontic tooth movement
IL-1RA	Afacan et al,7 2019	GCF	Upregulated at 28 d with both light and heavy force; modulated by force intensity
IL-1RA	Iwasaki et al,5 2009	GCF	Decreased IL-1RA was associated with faster movement; linked to IL-1β polymorphisms
IL-4	Giannopoulou et al, 200813	GCF	No significant change between orthodontic and control groups; IL-1β and IL-8 were elevated instead

^∗IL: Interleukin.

^†IL-1RA: Interleukin-1 receptor antagonist.

^‡GCF: Gingival crevicular fluid.

The temporal fluctuation in cytokine expression was another finding. According to studies such as Ratanasereeprasert et al,¹⁰ cytokine levels may be used as biomarkers to monitor the effectiveness of treatment and adjust force application because they show changes in gene expression and cytokine release over time. Moreover, there is limited understanding of the role anti-inflammatory cytokines, particularly IL-10, play in managing the inflammatory response, necessitating further research. Our review underscores the potential of cytokines as indicators for monitoring the progress of orthodontic treatment. Elevated IL-1β levels have been associated with accelerated bone resorption, whereas IL-10 and IL-1RA contribute to inflammation regulation, facilitating a balanced and controlled tooth movement process. By deciphering these cytokine patterns, orthodontists can refine treatment strategies, optimizing force application to reduce treatment duration and enhance patient comfort (Figure 6).

Figure 6.

Graphical representation of the cytokine timeline during orthodontic tooth movement. IL: Interleukin.

Conclusions

Our review emphasizes how important cytokines are for orthodontic tooth mobility and how they play a part in bone remodeling through localized anti-inflammatory and inflammatory mechanisms. Proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, have been found to rise dramatically in the early phases of therapy and are strongly correlated with force application and tooth movement speed. Furthermore, variations in cytokine expression between people and treatment modalities point to the possibility of more individualized orthodontic techniques. However, the necessity for larger-scale studies and established research methodologies is highlighted by the limited sample sizes and methodological variations among studies. Gaining insight into the role of cytokines in orthodontic treatment could revolutionize our approach to tooth movement. Elevated IL-1β levels are associated with accelerated bone resorption, whereas IL-10 and IL-1RA play a role in moderating inflammation, ensuring the process remains balanced and controlled. By understanding these dynamics, orthodontists can adjust the forces applied to teeth, potentially reducing treatment duration and enhancing patient comfort. In the future, therapies that modulate cytokine activity, whether through pharmaceuticals or tailored force modifications, could make orthodontic care more precise, effective, and patient-friendly, and should concentrate on the genetic variables influencing cytokine responses, the dynamic interplay between pro- and anti-inflammatory mediators, and the long-term effects of orthodontic pressures on cytokine production (Table 3).

Table 3.

Summary of cytokine roles and expression during orthodontic tooth movement.

Cytokine	Functional Role	Timing of Expression	Clinical Implications
IL∗-1β	Potent proinflammatory mediator; activates osteoclasts via receptor activator of nuclear factor κB ligand pathway	Peaks within 24-48 h after force application	Initiates bone resorption and rapid early tooth movement
IL-6	Promotes inflammatory cell recruitment and osteoclastogenesis	Elevates within 1-3 d	Enhances bone remodeling activity
IL-1 receptor antagonist	Natural antagonist of IL-1β; suppresses its inflammatory effects	Early response (2-4 d)	Helps regulate excessive inflammation and bone resorption
IL-10	Anti-inflammatory cytokine; downregulates IL-1β and IL-6	Increases after 3-7 d	Facilitates the resolution of inflammation and promotes bone healing
IL-4	Suppresses proinflammatory cytokines; inhibits osteoclastogenesis	Late phase (7-14 d)	Aids in tissue remodeling and limits root resorption

^∗IL: Interleukin.

Future Perspective

Looking into the future, our analysis not only traces the inflammatory chronology of OTM but also lays the path for cytokine application in therapeutic situations. By emphasizing the synchronized increase of anti-inflammatory cytokines such as IL-10 and IL-1RA during the resolution phase, our research suggests their potential as therapeutic targets, rather than merely markers, to enhance patient outcomes. Emerging evidence, including research on omega-3 fatty acids, indicates that these cytokines can be influenced through noninvasive methods like functional foods or nutraceuticals, which may aid in healing and minimize side effects like root resorption without hindering tooth movement. These pathways, affected by nuclear factor κ activated B cells and peroxisome proliferator-activated receptor γ signaling, provide a biological basis for developing future adjuncts that work alongside mechanical force application.¹⁶ Furthermore, the consistent expression patterns in GCF, saliva, and serum endorse the use of these cytokines as real-time, noninvasive biomarkers for personalized treatment planning. The next step involves conducting larger, multicenter studies with standardized protocols to confirm these findings, refine biomarker thresholds, and investigate gene-cytokine interactions. With these insights, the field is moving toward a future in which orthodontic care is not only mechanical but also molecularly guided—more precise, more comfortable, and more attuned to each patient’s biology.

Disclosure

None of the authors reported any disclosures.