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The long non-coding RNA (LncRNA) X-inactive specific transcript (XIST) regulates the biological process of osteoclasts and the process of related diseases. This study was attempted to investigate the mechanism of LncRNA XIST acting in osteoclast formation and orthodontic induced inflammatory root resorption (OIIRR). The compression force (CF) -induced cell model and the orthodontic tooth movement (OTM) rat model were designed and established in this study. The expression of LncRNA XIST, miR-130b-3p, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as well as osteoclast related marker genes and inflammatory factors level were measured in this study. The interaction among LncRNA XIST, microRNA-130b-3p (miR-130b-3p) and PTEN were researched through luciferase activity and western blot assay. Pathological sections were used to analyze root resorption and osteoclast formation. The OTM rat model was successfully constructed, which was characterized by increased tooth spacing and increased root resorption pits. PTEN and LncRNA XIST was overexpressed in OTM group. Mechanism analysis showed that the overexpression of LncRNA XIST enhanced the PTEN level by sponging miR-130b-3p. The overexpression of LncRNA XIST increased the secretion of inflammatory factors and positive osteoclasts number, but inhibited the differentiation of osteoclasts by sponging miR-130b-3p and promoting the level of PTEN. This finding demonstrates that LncRNA XIST regulates osteoclast formation and aggravated OIIRR through miR-130b-3p/PTEN axis, suggesting that LncRNA XIST may be used as potential targets for OIIRR therapy.

Introduction: External apical root resorption (EARR) is often an undesirable sequela of orthodontic treatment. Prior studies have suggested a substantial link between EARR and certain genetic components. Single nucleotide polymorphisms (SNPs) may play a role as predisposing factors. This study aimed to investigate the potential association between EARR and various SNPs., Methods: The study included 218 orthodontic participants of all malocclusions who had available pretreatment and posttreatment panoramic radiographs. The most severely affected maxillary incisor on the radiograph was assessed for EARR using a 0-4 categorical scale. DNA was taken from the saliva samples of the participants, and the SNPs were analyzed using polymerase chain reaction and TaqMan chemistry. Statistical testing was performed to verify any associations with EARR (P <0.05)., Results: From all genes tested, the rs678397 SNP of ACT3N (P = 0.003) and the rs1051771 SNP of TSC2 (P = 0.03) were significantly associated with EARR. No association could be established between other polymorphisms and EARR. In addition, patients with Class III malocclusion and extended treatment times were at increased risk of developing EARR., Conclusions: Our results support the concept of gene polymorphisms as risk factors in EARR. In particular, a significant association was found between ACT3N and TSC2 and EARR. Clinically, predisposing risk factors for EARR should be assessed for each patient., (Copyright © 2024 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to analyze the scientific production of genetic polymorphisms and external apical root resorption (EARR) to establish main findings, geographic trends, and research gaps for possible future investigations., Methods: Unrestricted publications were searched using the Scopus database (March 2023) to include studies that addressed the association between genetic polymorphisms and EARR. Case-control, cohort, cross-sectional, and review studies were considered eligible. The softwares VOS viewer™ and Bibliometrix were used for data analysis., Results: Of the 44 studies analyzed, "Iglesias-Linares A" was the most cited author. The University of Seville (Spain) conducted the most research on this topic. Brazil, Spain, and the USA were the leading countries in terms of citations. The most frequent term in the co-occurrence of keywords was "EARR." The journal American Journal of Orthodontics and Dentofacial Orthopedics presented a great relevance in the area, demonstrating a high number of publications. Several genetic polymorphisms have been investigated, with interleukins being the most studied., Conclusion: Endodontics is an area of research that should focus more on root resorption and genetic polymorphisms, as it still underexplored, compared to orthodontics. Polymorphisms have been studied as possible predictors of EARR caused by orthodontic tooth movement. However, the gap in the research indicates a need to search for new genes associated with EARR.

Objectives: Root resorption in permanent teeth is a common pathological process that often follows dental trauma or orthodontic treatment. More rarely, root resorption is a feature of genetic disorders and can help with diagnosis. Thus, the present review aims to determine which genetic disorders could induce pathological root resorptions and thus which mutated genes could be associated with them., Methods: We conducted a systematic review following the PRISMA guidelines. Articles describing root resorptions in patients with genetic disorders were included from PubMed, Embase, Web of Science, and Google Scholar. We synthesized the genetic disorder, the type, severity, and extent of the resorptions, as well as the other systemic and oral symptoms and histological features., Results: The synthetic analysis included 25 studies among 937 identified records. We analyzed 21 case reports, three case series, and one cohort study. Overall, we highlighted 14 different pathologies with described root resorptions. Depending on the pathology, the sites of resorption, their extent, and their severity showed differences., Conclusion: With 14 genetic pathologies suspected to induce root resorptions, our findings are significant and enrich a previous classification. Among them, three metabolic disorders, three calcium-phosphorus metabolism disorders, and osteolysis disorders were identified., (© 2024 Wiley Periodicals LLC.)

The tooth movement is a fundamental requirement during any orthodontic treatment. This study aimed to investigate the action and mechanism of strontium ranelate (SR) in orthodontic tooth movement (OTM). Rats were given SR by gavage daily, along with lentiviral vectors interfering with circBACH1 or miR-155-5p. Three weeks later, an OTM rat model was established. RANKL and osteoprotegerin (OpG) in serum were measured. The gap between the first and second molar and root resorption were examined. Osteoclast test was used; and root condition was examined. Detection of miR-155-5p, circBACH1, CLC7 and cathepsin K was performed. The binding of circBACH1 to miR-155-5p was verified. In OTM rats, circBACH1 was elevated (p<0.05) and miR-155-5p was silenced (p<0.05). SR reduced osteoclast activity (p<0.05) and improved root resorption (p<0.05) in OTM rats, which was enhanced by silenced circBACH1 (p<0.05) or elevated miR-155-5p (p<0.05). circBACH1 inhibited miR-155-5p expression (p<0.05). Silenced miR-155-5p reversed the ameliorative effect of circBACH1 on tooth root resorption in OTM rats (all p<0.05). SR modulates circBACH1/miR-155-5p to ameliorate root resorption and tooth fixation during OTM.

Background: External apical root resorption (EARR) is a common undesirable outcome of orthodontic treatment, this study aimed to identify genetic polymorphisms associated with the susceptibility to extreme orthodontic-induced EARR in a Korean population using extreme phenotype analysis sampling., Methods: Genomic DNA was isolated from the saliva of 77 patients who underwent orthodontic treatment involving two maxillary premolar extractions. The patients were divided into two groups based on EARR values measured on periapical radiographs: The significant resorption group (SG, EARR ≥ 4 mm) and the normal group (NG, EARR < 2 mm). In the NG group, patients with EARR < 1 mm were named the non-resorption group (NonG). Targeted next-generation sequencing was performed using the screened single nucleotide polymorphisms (SNPs), and firth logistic regression analysis was used to determine genetic associations with EARR. Haplotype-based association analysis was performed for specific SNPs., Results: SNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 were found to be significantly associated with severe EARR (p < 0.05, pre-Bonferroni correction p-values). Additionally, the haplotype CCA of rs17525809, rs208294, and rs1718119 P2RX7 had a higher frequency in the SG group., Conclusion: Extreme phenotype analysis has identified eleven SNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 that are associated with severe root resorption in the Korean population. These findings will contribute to the development of predictive diagnostic tools for identifying severe root resorption that may occur during orthodontic treatment., (© 2024. The Author(s).)

Objective: To assess the allele rs 1143634 in IL-1β and rs1800587 in IL-1α in patients for orthodontically induced external apical root resorption (EARR)., Material and Methods: Intra-oral periapical radiograph (IOPA) of maxillary incisors of 142 Patients were evaluated for resorption at two time points; before the start of fixed mechanotherapy (T1) and after one year of treatment (T2). The individuals with root resorption<2mm were categorized as a control group (group 1; n=90), and resorption>2mm were categorized as case group (group 2; n=52). Buccal swabs of all patients were taken and DNA could be isolated in 95 out of 142 samples (group 1 {n=58}, group 2 {n=37}), which were then screened for the selected two polymorphic targets to determine the nucleotide status of these targets. Tetra-primer ARMS PCR reactions were carried out using all 4 primers for each polymorphism., Results: rs11800587 was not associated with risk of EARR in any inheritance model. Chi-square test for association of alleles with EARR revealed that rs1143634 was associated with the risk of EARR in an allelic model in such a way that A allele of this SNP increased the risk of EARR 4 folds [OR=4.375; P=0.016]. However, the adjusted level of significance using the Holm-Bonferroni method for rs1143634 was P<0.010 for A and G comparison rendering the results non-significant., Conclusion: SNP rs1143634 and SNP rs11800587 were not associated with risk of EARR in any inheritance model., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Physiological root resorption is a common occurrence during the development of deciduous teeth in children. Previous research has shown that the regulation of the inflammatory microenvironment through autophagy in DDPSCs is a significant factor in this process. However, it remains unclear why there are variations in the autophagic status of DDPSCs at different stages of physiological root resorption. To address this gap in knowledge, this study examines the relationship between the circadian clock of DDPSCs, the autophagic status, and the periodicity of masticatory behavior. Samples were collected from deciduous teeth at various stages of physiological root resorption, and DDPSCs were isolated and cultured for analysis. The results indicate that the circadian rhythm of important autophagy genes, such as Beclin-1 and LC3, and the clock gene REV-ERBα in DDPSCs, disappears under mechanical stress. Additionally, the study found that REV-ERBα can regulate Beclin-1 and LC3. Evidence suggests that mechanical stress is a trigger for the regulation of autophagy via REV-ERBα. Overall, this study highlights the importance of mechanical stress in regulating autophagy of DDPSCs via REV-ERBα, which affects the formation of the inflammatory microenvironment and plays a critical role in physiological root resorption in deciduous teeth., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family., Methods: The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function., Results: The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity., Conclusion: A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.

Interferon regulatory factor 8 (IRF8), a transcription factor expressed in immune cells, functions as a negative regulator of osteoclasts and helps maintain dental and skeletal homeostasis. Previously, we reported that a novel mutation in the IRF8 gene increases susceptibility to multiple idiopathic cervical root resorption (MICRR), a form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function in osteoclastogenesis, we generated Irf8 knock-in ( KI ) mice using CRISPR/Cas9 technique modeling the human IRF8 G388S mutation. The heterozygous (Het) and homozygous (Homo) Irf8 KI mice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to wild-type (WT) mice. The Irf8 KI Het and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients, Irf8 KI Het and Homo mice demonstrated significantly increased osteoclast formation and resorption activity in vivo and in vitro when compared to WT mice. The oral ligature-inserted Het and Homo mice displayed significantly increased root resorption and osteoclast-mediated alveolar bone loss compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of IRF8 G388S mutation to inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts, as well as its impact on autophagy-related pathways of osteoclast differentiation. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into the IRF8 mutation associated with MICRR. IRF8 G388S mutation mainly affects osteoclastogenesis while sparing immune cell development and function. These insights extend beyond oral health and significantly advance our understanding of skeletal disorders mediated by increased osteoclast activity and IRF8's role in osteoclastogenesis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: External apical root resorption (EARR) is a multifactorial disorder with adverse clinical outcomes in orthodontic practices often resulting in significant root shortening. This study examined the effect that specific single nucleotide polymorphisms (SNPs) have on the risk of developing EARR in orthodontic patients in X. We also evaluated how other selected patient- and treatment-related factors may contribute to root resorption in these patients., Setting/sample: Patients included in this case-control study were treated at the University of Alabama at Birmingham School of Dentistry, Department of Orthodontics., Methods: Panoramic radiographs were used to measure root resorption of the maxillary incisors. EARR was recorded when at least 20% of the root length had been lost with orthodontic treatment. Factors evaluated for association with EARR included ethnicity, sex, age, dental and skeletal classifications, ANB, U1-SN, overjet, treatment type and time, and SNPs in IL-1A (rs1800587), IL-1B (rs1143634), IL-1RN (rs419598), P2RX7 (rs1718119 and rs2230912), IRAK1 (rs1059703) and CASP1 (rs530537, rs580253 and rs554344). Chi-square test, Student's t test, Wilcoxon test, Benjamin-Hochberg false discovery rate (FDR) adjustment and logistic regression were used to analyse the data. The significance level was defined as P < .05., Results: We found that extraction treatment protocol and dental classification displayed significant association with root resorption. Furthermore, the GG genotype of IL-1A rs1800587 variant (in individuals with an increased overjet) predisposed Caucasians to EARR. While CASP1 (rs530537) variant may contribute to the risk of root resorption, it was not statistically significant after FDR adjustment (P = .09)., Conclusions: Both patient- and treatment-related factors contributed to EARR., (© 2023 The Authors. Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Introduction: Multiple idiopathic cervical root resorption (MICRR) is a disease with an unknown etiology that causes invasive cervical root resorption in multiple teeth. Although previous MICRR genomic studies have identified candidate gene variants, the etiology of the condition remains poorly understood. In the present study, we investigated the genetic causality of MICRR to explore candidate variants., Methods: Saliva samples from a family containing 2 affected and two unaffected subjects with the dominant transmission of MICRR were subjected to whole-exome sequencing., Results: As a result, we identified novel candidate variants of 10 genes. Each variant was confirmed by Sanger sequencing. Among them, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines classified doublecortin domain containing 1 (c.1099 C > T) and β-defensin 114 (c.189 T > G) as "pathogenic," and solute carrier family 45 member 2 (c.152&#95;153del) as "likely pathogenic.", Conclusions: These results provide new insight to help clarify the pathogenesis of MICRR, and the variants could be applied for further investigation to understand invasive cervical root resorption., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

This study evaluated the association between single-nucleotide polymorphisms (SNPs) in vitamin-D-related genes and the amount of external apical root resorption linked to orthodontic treatment. One hundred and forty-three individuals were assessed. The amount of external apical root resorption of upper central incisors (EARR inc ) and lower first molars (EARR mol ) were evaluated in radiographs. Seven SNPs were genotyped across four genes including the vitamin D receptor [VDR], group-specific component [GC], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], and cytochrome P450 family 24 subfamily A member 1 [CYP24A1]. Linear regressions were implemented to determine allele-effects on external apical root resorption. Individuals carrying the AA genotype in VDR rs2228570 had a 21% higher EARR mol than those having AG and GG genotypes (95% CI: 1.03,1.40). EARR mol in heterozygous rs2228570, was 12% lower than for homozygotes (95%CI: 0.78,0.99). Participants with the CCG haplotype (rs1544410-rs7975232-rs731236) in VDR had an EARR mol 16% lower than those who did not carry this haplotype. Regarding CYP27B1 rs4646536, EARR inc in participants who had at least one G allele was 42% lower than for homozygotes AA (95%CI: 0.37,0.93). Although these results did not remain significant after multiple testing adjustment, potential associations may still be suggested. Further replication studies are needed to confirm or refute these findings., (© 2023 The Authors. European Journal of Oral Sciences published by John Wiley & Sons Ltd on behalf of Scandinavian Division of the International Association for Dental Research.)

A rare case of extensive multiple idiopathic cervical root resorption with potential genetic predisposition was presented. A heathy 19-year-old Chinese male with no contributory medical or family/social history complained of pain during mastication that lasted for several months. Oral examination identified 7 missing teeth and external cervical root resorption involving 9 teeth. Comparison of orthopantomograms taken in May 2021 and February 2022 identified that cervical root resorption occurred in 22 teeth. Resorption commenced at the cementoenamel junction and progressed rapidly over the 9-month period. Laboratory test results were within normal limits. Trio-based whole-exome sequencing showed a missense mutation c.5630 C > T in the filamin A (FLNA) gene at chromosome X of the subject. This is suggestive of the possibility of sex-linked recessive inheritance. This is the first study to report FLNA mutation in human subjects with cervical root resorption involving multiple teeth., (Copyright © 2022 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Prediction of susceptibility to Orthodontically Induced External Apical Root Resorption (OIEARR) has been hampered by the complex architecture of this multifactorial phenotype. The aim of this study was to analyze the impact of the interaction of multiple variables in the susceptibility to OIEARR., Methods: The study evaluated 195 patients requiring orthodontic treatment. Nine clinical and treatment variables, single nucleotide polymorphisms (SNPs) from five genes and variables interactions were analyzed as risk factors for OIEARR using a multiple linear regression model., Results: The model explained 29% of OIEARR variability (ANOVA: p < 0.01). Duration of treatment was the most important predictor and gender was the second, closely followed by premolar extraction. For genes encoding osteoprotegerin (OPG), the receptor activator of nuclear factor κ B (RANK) and the IL1 receptor antagonist (IL1RN), the effect of analyzed variants changed from protective to deleterious depending on the duration of treatment and the age of the patient., Conclusions: This work shows that in OIEARR the impact of genetic susceptibility factors is dynamic changing according to clinical variables., (© 2022. The Author(s).)

Patients with periodontitis undergoing orthodontic therapy may suffer from undesired dental root resorption. The purpose of this in vitro study was to investigate the molecular mechanisms resulting in PD-L1 expression of cementoblasts in response to infection with Porphyromonas gingivalis ( P. gingivalis ) peptidoglycan (PGN) and compressive force (CF), and its interaction with hypoxia-inducible factor (HIF)-1α molecule: The cementoblast (OCCM-30) cells were kinetically infected with various concentrations of P. gingivalis PGN in the presence and absence of CF. Western blotting and RT-qPCR were performed to examine the protein expression of PD-L1 and HIF-1α as well as their gene expression. Immunofluorescence was applied to visualize the localization of these proteins within cells. An HIF-1α inhibitor was added for further investigation of necroptosis by flow cytometry analysis. Releases of soluble GAS-6 were measured by ELISA. P. gingivalis PGN dose dependently stimulated PD-L1 upregulation in cementoblasts at protein and mRNA levels. CF combined with P. gingivalis PGN had synergistic effects on the induction of PD-L1. Blockade of HIF-1α inhibited the P. gingivalis PGN-inducible PD-L1 protein expression under compression, indicating an HIF-1α dependent regulation of PD-L1 induction. Concomitantly, an HIF-1α inhibitor decreased the GAS-6 release in the presence of CF and P. gingivalis PGN co-stimulation. The data suggest that PGN of P. gingivalis participates in PD-L1 up-regulation in cementoblasts. Additionally, the influence of compressive force on P. gingivalis PGN-induced PD-L1 expression occurs in HIF-1α dependently. In this regard, HIF-1α may play roles in the immune response of cementoblasts via immune-inhibitory PD-L1. Our results underline the importance of molecular mechanisms involved in bacteria-induced periodontics and root resorption.

To investigate the genetic association in a sample of replanted teeth, it is necessary to observe the extreme phenotypes, such as, teeth that underwent functional healing and those extracted due to severe external root resorption. Thus, this study aimed to investigate the association of age of the patients, root development, storage media, and polymorphisms in the interleukin 4 (IL4) and interleukin 6 (IL6) genes with teeth that presented extreme outcomes, as functional healing or extraction, in a group whose replantation techniques did not follow the International Association of Dental Traumatology (IADT) 2012 guidelines. Forty-three avulsed and replanted teeth that did not follow IADT 2012 guidelines and underwent functional healing or were extracted were included. Periapical radiographs employed for this study were taken soon after tooth replantation and after 1 year. For genotypic IL4 and IL6 genes analysis, DNA of oral mucosa cells was extracted. Real-time- PCR performed for genotyping polymorphisms in IL4 and IL6 genes. Clinical and genetic variables were analyzed by the Chi-square test and the "Z" test. P values < .05 were considered significant. The results showed that functional healing and extraction were associated with storage media and with the rs2243268 of IL- 4 gene polymorphisms. As conclusion, the C rs2243268 allele of IL4 gene may have a positive relationship with functional healing teeth that were replanted not following the 2012 IADT guidelines. Keeping the tooth dry is associated to a fast loss of avulsed and replanted teeth after 1-year follow-up.

Background: MicroRNAs (miRNAs) are involved in the regulation of osteoclast biology and several pathogenic progression. This study aimed to identify the role of miR-26a in osteoclastogenesis and orthodontically induced inflammatory root resorption(OIIRR)., Methods: Rat orthodontic tooth movement (OTM) model was established by ligating a closed coil spring between maxillary first molar and incisor, and 50 g orthodontic force was applied to move upper first molar to middle for 7 days. Human periodontal ligament (hPDL) cells were isolated from periodontium of healthy donors, and then subjected to compression force (CF) for 24 h to mimic an in vitro OTM model. The levels of associated factors in vivo and in vitro were measured subsequently., Result: The distance of tooth movement was increased and root resorption pits were occurred in rat OTM model. The expression of miR-26a was decreased in vivo and vitro experiments. CF treatment enhanced the secretion of inflammatory factors receptor activator of nuclear factor-kappa B ligand (RANKL) and IL-6, osteoclast marker levels, and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, while miR-26a overexpression reversed these results. Furthermore, miR-26a overexpression inhibited the osteoclastogenesis and rescued the root resorption in OTM rats through inhibition of Jagged1. Additionally, Runx1 could bind to miR-26a promoter and promote its expression, thereby suppressing the osteoclastogenesis., Conclusion: We concluded that Runx1/miR-26a/Jagged1 signaling axis restrained osteoclastogenesis and alleviated OIIRR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To perform a systematic review/meta-analysis to elucidate the scientific basis for the association between genetic variations and risk of external apical root resorption (EARR) in orthodontic patients., Materials and Methods: Four databases (PubMed, Web of Science, Scopus, LILACS) were electronically searched until November 22, 2020, followed by manual and gray literature search. Case-control or cross-sectional studies that evaluated genes involved in the susceptibility of orthodontic patients to EARR were eligible. Two reviewers applied the inclusion and exclusion criteria, extracted qualitative data, as well as assessed methodological quality using instrument proposed for genetic studies. For synthesis results, narrative and quantitative data (meta-analysis) were performed. The certainty of the evidence was tested using the GRADE Working Group approach., Results: Of 201 articles in total, 16 studies were included in the review. Of these, 11 presented moderate and 5 of high methodological quality. In the narrative analysis, from 16 studies, 15 studies (10 genes) showed a significant association with EARR and 9 studies were included in the meta-analysis. Only the polymorphism rs208294 in P2RX7 (dominant model) was associated with EARR (OR = 0.52, 95%CI = 0.29-0.95, p = 0.03) and presented a very low certainty of the evidence., Conclusion: Narrative analyses of individual studies demonstrated an association of many genes. The number of studies for each genetic variation was very low, and methodological heterogeneity between the studies was observed. Quantitative analyses (meta-analysis) could only show an involvement for P2RX7 (rs208294) in the risk of orthodontic patients to EARR at a very low certainty of evidence. (CRD42018085411)., Clinical Relevance: The knowledge regarding the molecular aspects involved in the etiology of EARR will allow orthodontists to use a personalized treatment and early diagnosis of risk patients. This systematic review demonstrates that more studies are necessary to unravel the role of genetic variation for patients' risk to EARR during orthodontic tooth movement., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The absence or presence of root resorption on the root surface of a replanted tooth indicates an immune-inflammatory reaction. Since interleukin-6 (IL-6) is considered an inflammatory marker in bone resorption, this study aimed to investigate the association between clinical variables and polymorphisms in IL6, with the outcome of replanted teeth at 1-year follow-up. Altogether, 127 avulsed teeth that were replanted and had their root canals treated were selected for this study. Periapical radiographs were taken after replantation and after 1 year. Real-time PCR was used to genotype IL6 polymorphisms. Chi-square and 'Z' tests were performed to verify the association between genetic variables and the prognosis of replanted teeth (P < 0.05). An association was observed between the rs2069843 polymorphism of IL6 and the outcome of replanted teeth (P < 0.05). The rs2069843 polymorphism of IL6 may influence the outcome of avulsed and replanted teeth in the first year post-trauma., (© 2021 Australian Society of Endodontology Inc.)

Background and Objective: Root resorption is an unavoidable side effect of orthodontic tooth movement. The mechanism of root resorption is similar to bone resorption; the odontoclasts share similar characteristics with osteoclasts (OCs). MicroRNAs (miRNAs) such as miR-155-5p play an important role in OC differentiation, but the underlying molecular mechanism of miR-155-5p in this process is not fully understood. We found that the miR-155-5p seed sequences were complementary to a sequence conserved in the 3-untranslated region of CXCR2 mRNA. In this study, we explored the molecular mechanism underlying the effect of miR-155-5p on OC differentiation by targeting CXCR2., Materials and Methods: In this study, we divided the orthodontic patients into mild, moderate, and severe groups according to the severity of root resorption. The gingival crevicular fluid (GCF) of patients in different groups was collected, and the expression levels of dentin phosphoprotein (DPP) were detected by ELISA, and the expression levels of CXCR2 and miR-155-5p in GCF were detected by real-time quantitative PCR (qRT-PCR). The relationship between miR-155-5p and CXCR2 was verified by double luciferase. We analyzed changes of CXCR2 and miR-155-5p expression after transfection of miR-155-5p mimic and inhibitor into RAW264.7 cells induced by receptor activator of nuclear factor-κB ligand (RANKL) through qRT-PCR and western blotting. The effect of miR-155-5p on OC differentiation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining. QRT-PCR and western blotting were used to analyze expression of the osteoclastic bone resorption-related enzymes carbonic anhydrase 2 (CA II), matrix metalloproteinase-9 (MMP-9), and cathepsin K. To further confirm the direct targeting effect of CXCR2 by miR-155-5p, we blocked CXCR2 using si-CXCR2 in RANKL-induced RAW264.7 cells., Results: Dentin phosphoprotein levels were consistent with the trend of miR-155-5p changes, and the trend of CXCR2 expression was opposite to miR-155-5p changes. miR-155-5p can be directly targeted to act on CXCR2. The expression of miR-155-5p was significantly downregulated in differentiated OCs. MiR-155-5p inhibited OC differentiation, and downregulated CA II, MMP-9, and cathepsin K expression at the protein and mRNA levels., Conclusions: In summary, the results of this study suggested that miR-155-5p inhibited OC differentiation by targeting CXCR2, thus reducing root resorption in orthodontics. MiR-155-5p can be used as an effective target for avoiding or reducing the degree of root resorption in orthodontic treatment., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

External apical root resorption (EARR) is one of the most serious complications associated with orthodontic treatment. The aim of the study was to analyze the relationships between selected single nucleotide polymorphisms (SNPs) in Interleukin 1 receptor antagonist ( IL1RN ), purinoreceptor P2X7 ( P2RX7 ) and EARR in patients after orthodontic treatment. The study comprised 101 patients who underwent a complex orthodontic treatment with a combination of fixed appliances. Roots were measured based on orthopantomograms and lateral cephalometric radiographs taken before and at the end of the treatment using diagnostic software. Proportional measurements of selected teeth were made using the modified Linge and Linge methods. Based on the presence or absence of EARR, patients were divided into two groups: control group, 61 patients without EARR (with 0.90 ≤ rRCR ≤ 1.00), and EARR group, 40 patients with EARR (rRCR < 0.90). Root resorption in selected groups was also evaluated with the scores of Malmgren and Levander. SNP analysis was performed using the real-time polymerase chain reaction (PCR) method. The analysis indicated that a specific haplotype of P2RX7 (rs208294) and IL1RN (rs419598) modified the risk of EARR development ( p < 0.05), with a Bonferroni correction. The analysis of the P2RX7 and IL1RN gene polymorphisms showed that the presence of SNPs of these genes may predispose individuals to EARR. These findings indicate that EARR is a complex condition influenced not only by environmental factors and needs further study on the genetic risk factors.

This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8 G388S ) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8 G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8 WT control. Further, similar to subjects with heterozygous IRF8 G388S mutation, Irf8 +/- mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8 -/- and Irf8 +/- mice when compared with Irf8 +/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Objectives: The aim of this study was to investigate the association of clinical variables and polymorphisms in the RANKL, RANK, and OPG genes with external apical root resorption (EARR)., Methods: The sample was composed of 338 unrelated patients of both sexes, average age 14.9 years (range 8-21) with Class II Division 1 malocclusion, orthodontically treated. Periapical radiographs of the maxillary central incisor with the longer root (reference tooth) were taken before treatment and 6 months after starting treatment. DNA was extracted from buccal epithelial cells with the use of 10 mol/L ammonium acetate and 1 mmol/L EDTA. The analysis of 42 polymorphisms in the RANKL, RANK, and OPG genes was performed by means of real-time polymerase chain reaction. Univariate and multivariate analyzes were performed to verify the association of clinical and genetic variables with EARR (P <0.05)., Results: The initial root length and patient age were associated with EARR. Considering the study of polymorphisms of RANKL, no significant association was found of genetic polymorphisms with EARR. For RANK polymorphisms, only rs12455775 was associated with EARR. Regarding OPG polymorphisms, an association of rs3102724, rs2875845, rs1032128, and rs3102728 with EARR was found. After multivariate analysis, the initial root length, rapid maxillary expansion, and rs3102724 of the OPG gene were associated with EARR., Conclusions: Longer roots of upper central incisors and rapid maxillary expansion, as well as allele A of the rs3102724 polymorphism of the OPG gene, were associated with EARR in the study population., (Copyright © 2019 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

External apical root resorption (EARR) induced by orthodontic treatment and chronic periodontitis (CP) are complex phenotypes dependent on the interaction of multiple genetic and non-genetic risk factors. Apart from different environmental triggers, these phenotypes are caused by antagonistic biological mechanisms involving local immunoinflammatory reaction and alveolar bone metabolism, for which IL1 have a prominent role. Whereas EARR benefits from bone remodelling, CP is characterized by osteolytic damaged. Our aim was to verify if these two phenotypes have opposite genetic profiles, considering the most frequently analysed polymorphisms for both diseases. A review of the literature was performed searching for the association of rs1800587 from Interleukin-1 alpha (IL1A) gene and rs1143634 from interleukin-1 beta (IL1B) gene with EARR and CP. The electronic search included MEDLINE/PubMed, EBSCOhost, Cochrane and Web of Science databases. Twenty four articles met the inclusion and exclusion criteria. For IL1B polymorphism, two out of seven studies found a significant statistical association between EARR and CC genotype, whether for CP, there were eighth out of fifteen references describing a statistically significant associations with T allele. For IL1A variant, no significant association with EARR was described. In conclusion, literature review suggests that for IL1B SNP rs1143634, EARR and CP have an opposite genetic profile. For IL1A SNP, our hypothesis could not be confirmed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Animal studies suggest that the dental follicle (DF) plays a major role in tooth eruption. However, the role of the DF during tooth impaction and related root resorptions in adjacent teeth is not clear. The hypothesis for the present study is that expression of regulatory factors involved in the bone remodelling process necessary for tooth eruption may differ between dental follicles from teeth with different clinical situations. We have analysed the gene expression profiles in the DF obtained from impacted canines, with (N = 3) or without (N = 5) signs of root resorption, and from control teeth (normal erupting teeth, mesiodens) (N = 3). DF from 11 patients (mean age: 13 years) obtains at the time of surgical exposure of the tooth. Due to the surgical time point, all teeth were in a late developmental stage. Gene expression related to osteoblast activation/bone formation, osteoclast recruitment and activation was analysed by RTqPCR. Genes related to bone formation (RUNX2, OSX, ALP, OCN, CX43) were highly expressed in all the samples, but osteoclast recruitment/activation markers (OPG, RANKL, MCP-1, CSF-1) were negligible. No apparent patterns or significant differences in gene expression were found between impacted canines, with or without signs of root resorption, or when compared to control teeth. Our results suggest the DF regulation of osteoclastic activity is limited in the late pre-emergent stage of tooth development, irrespective if the tooth is normally erupting or impacted. We suggest that the follicle may have an important regulatory function for alveolar bone formation in the final eruption process and CX43-gap junction communication could be an important signalling pathway.

Aim: To investigate the association of clinical variables and polymorphisms (tag SNPs) in the interleukin 4 (IL4) gene, with the prognosis of avulsed and replanted teeth., Methodology: Ninety-four patients who suffered avulsion and had their teeth replanted and endodontically treated were included. Periapical radiographs were obtained soon after tooth replantation and after 1 year. For genotypic IL4 gene analysis, the DNA from oral mucosa cells was collected, and polymorphisms were investigated by real-time PCR. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables and the outcome of the replanted teeth (P < 0.05)., Results: After multivariate analysis, extra-alveolar time longer than 1 h was significantly associated with external root resorption. No significant association was observed between IL4 gene polymorphisms and root resorption., Conclusion: No association between root resorption and IL4 gene polymorphisms was observed. An extra-alveolar time of more than 1 h was associated with a susceptibility for external root resorption. Replanting the tooth in its socket immediately is the most important factor to maintain a healthy root surface., (© 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Introduction: The absence or presence of root resorption on the surface of a replanted tooth indicates an immune-inflammatory reaction. Recent research even suggests the participation of host predominant immunologic profile on types of resorptions detected on the root surface. Because interleukin 4 (IL-4) is an important anti-inflammatory cytokine, this study aimed to investigate the association of clinical variables and polymorphisms in IL4 with types of resorption of replanted teeth after 1 year of follow-up., Methods: One hundred twenty-seven avulsed teeth that were replanted were selected. Periapical radiographs were taken after replantation and for 1 year to detect the types of root resorption. Real-time polymerase chain reaction was used to genotype IL4 polymorphisms. The χ 2 and Z tests were performed to verify the association of clinical and genetic variables with the outcomes of replanted teeth (P < .05)., Results: An association was observed of extra-alveolar time, storage medium, and development of the root (P < .05), but not of IL4 polymorphisms, with the outcomes of replanted teeth (P > .05)., Conclusions: Extraoral time, storage medium, and development of the root, but not IL4 polymorphisms, may influence the types of resorption of avulsed and replanted teeth in the first year after trauma., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The hypothesis of this study was that multiple factors are dominant in causing external apical root resorption (EARR). The objective of this investigation was to better understand the clinical factors that may lead to EARR., Methods: Maxillary cone-beam computed tomography scans of 18 subjects who were treated with bilateral canine retractions during orthodontics were used to calculate EARR. The subjects were treated using well-calibrated segmental T-loops for delivering a 124-cN retraction force and the moment-to-force ratio suitable for moving the canine under either translation or controlled tipping. The subjects' age, sex, treatment duration, and genotype were collected., Results: Six subjects of the 18 showed definite EARR, meaning that load was not the only causing factor. All 5 subjects with the genotype identified had GG genotype of IL-1β rs11143634, indicating that people with this genotype may be at high risk. Longer treatment duration, female sex, and older age may also contribute to EARR, although the findings were not statistically significant., Conclusions: EARR appears to be related to multiple factors. The orthodontic load and the genotype should be the focuses for future studies., (Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and genetic or familial susceptibility. Current studies are undermined by methodological and interpretative errors, especially regarding the diagnosis and measurements of root resorption from orthopantomographs and cephalograms. Samples are heterogeneous insofar as they comprise different clinical operators, varied types of planning, and in insufficient number, in view of the prevalence of tooth resorptions in the population. Nearly all biological events are coded and managed through genes, but this does not mean tooth resorptions are inherited, which can be demonstrated in heredograms and other methods of family studies. In orthodontic root resorption, one cannot possibly determine percentages of how much would be due to heredity or genetics, environmental factors and unknown factors. There is no need to lay the blame of tooth resorptions on events taking place outside the orthodontic realm since in the vast majority of cases, resorptions are not iatrogenic. In orthodontic practice, when all teeth are analyzed and planned using periapical radiography or computerized tomography, and when considering all predictive factors, tooth resorptions are not iatrogenic in nature and should be considered as one of the clinical events inherent in the treatment applied.

Root resorption is a pathological process of multifactorial origin related to the permanent loss of dental root structure in response to a mechanical, inflammatory, autoimmune or infectious stimulus. External apical root resorption (EARR) is a frequent clinical complication secondary to orthodontic tooth movement; apart from variables related to treatment, environmental factors and/or interindividual genetic variations can confer susceptibility or resistance to its occurrence. In this context, genetic predisposition has been described as an etiological factor, together with mechanical factors derived from orthodontic treatment. In recent years, international research groups have determined the degree of influence of some genetic biomarkers in defining increased/reduced susceptibility to postorthodontic EARR. The influences of the IL1 gene cluster (IL1B, IL1A, IL1RN, IL6), P2RX7, CASP1, OPG (TNFRSF11B), RANK (TNFRSF11A), Osteopontin (OPN), TNFα, the vitamin D receptor (TaqI), TNSALP and IRAK1 have been analyzed. The objective of the present review study was to compile and analyze the latest information about the genetic background predisposing to EARR during orthodontic treatment. Genetics-based studies along with other basic science research in the field might help to clarify the exact nature of EARR, the influence of genetic inheritance and possibly lead to the prevention or even eradication of this phenomenon during orthodontic treatment.

External apical root resorption during orthodontic treatment implicates specific molecular pathways that orchestrate nonphysiologic cellular activation. To date, a substantial number of in vitro and in vivo molecular, genomic, and proteomic studies have supplied data that provide new insights into root resorption. Recent mechanisms and developments reviewed here include the role of the cellular component-specifically, the balance of CD68 + , iNOS + M1- and CD68 + , CD163 + M2-like macrophages associated with root resorption and root surface repair processes linked to the expression of the M1-associated proinflammatory cytokine tumor necrosis factor, inducible nitric oxide synthase, the M1 activator interferon γ, the M2 activator interleukin 4, and M2-associated anti-inflammatory interleukin 10 and arginase I. Insights into the role of mesenchymal dental pulp cells in attenuating dentin resorption in homeostasis are also reviewed. Data on recently deciphered molecular pathways are reviewed at the level of (1) clastic cell adhesion in the external apical root resorption process and the specific role of α/β integrins, osteopontin, and related extracellular matrix proteins; (2) clastic cell fusion and activation by the RANKL/RANK/OPG and ATP-P2RX7-IL1 pathways; and (3) regulatory mechanisms of root resorption repair by cementum at the proteomic and transcriptomic levels.

Objective: Genes, involved in the modulation of inflammatory response and bone remodeling, play a role in the development of postorthodontic external apical root resorption (EARR). The aim of our study was to analyze possible associations between seven single nucleotide polymorphisms (SNPs) in interleukin-17A (IL-17), osteopontin (SPP1), purinoreceptor P2X7 (P2RX7), and tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) genes and EARR in children after orthodontic treatment., Subjects and Methods: This case-control study comprised 99 orthodontically treated patients (69 controls and 30 subjects with EARR). Genotype determinations of rs2275913, rs11730582, rs9138, rs208294, rs1718119, rs3102735, and rs2073618 were based on polymerase chain reaction using 5' nuclease TaqMan ® assays., Results: While no significant differences were observed in allele or genotype frequencies of all seven studied SNPs, specific haplotype of P2RX7 (rs208294 and rs1718119) modified the risk of EARR development (P < 0.05). In addition, the length of treatment with a fixed orthodontic appliance positively correlated with the presence of EARR (P < 0.05)., Conclusions: Although the effect of individual SNPs studied on the EARR development was not confirmed in the Czech population, complex analysis suggested that variability in the P2RX7 gene and the length of orthodontic treatment may be important factors contributing to the etiopathogenesis of postorthodontic EARR., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To determine whether orthodontic treatment with removable aligners vs fixed orthodontic appliances is associated with a different frequency of orthodontically induced external apical root resorption (OIEARR) when genetic, radiographic, and clinical factors are accounted for., Materials and Methods: Three hundred seventy-two orthodontic patients treated with removable aligners (Invisalign) or fixed appliances were genetically screened for interleukin 1B gene (IL1B) (rs1143634), interleukin 1 receptor antagonist gene (IL1RN) (rs419598), and osteopontin gene (SPP1) (rs9138/rs11730582). Twelve clinical variables, potentially associated with OIEARR, were also considered. Subjects were divided according to the presence of radiographically determined OIEARR (>2 mm). The association between OIEARR and appliance type, and radiographic, clinical and genetic factors, was assessed using backward stepwise conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported., Results: Reliability of the methods was adequate. Clinical case complexity (American Board of Orthodontics [ABO] Discrepancy Index) (OR: 1.032; 95% CI: 1.005-1.061; P = .021) and extent of incisor apical displacement in the sagittal plane (OR: 1.478; 95% CI: 1.285-1.699; P = .001) were associated with an increased OIEARR risk. After adjusting for associations between clinical/radiographic/genetic factors, there were no statistically significant differences with respect to OIEARR or type of orthodontic appliance used, whether removable aligners or fixed appliances (OR: 1.662; 95% CI: 0.945-2.924; P = .078). Only subjects homozygous for the T allele of IL1RN (rs419598) were more prone to OIEARR during orthodontic treatment (OR: 3.121; CI: 1.93-5.03; P < .001)., Conclusions: A similar OIEARR predisposition was identified using either removable aligners (Invisalign) or fixed appliances.

When orthodontic patients desire shorter treatment times with aesthetic results and long-term stability, it is important for the orthodontist to understand the potential limitations and problems that may arise during standard and/or technology-assisted accelerated treatment. Bone density plays an important role in facilitating orthodontic tooth movement (OTM), such that reductions in bone density can significantly increase movement velocity. Lifestyle, genetic background, environmental factors, and disease status all can influence a patients' overall health and bone density. In some individuals, these factors may create specific conditions that influence systemic-wide bone metabolism. Both genetic variation and the onset of a bone-related disease can influence systemic bone density and local bone density, such as observed in the mandible and maxilla. These types of localized density changes can affect the rate of OTM and may also influence the risk of unwanted outcomes, i.e., the occurrence of dental external apical root resorption (EARR).

Objective: To evaluate the relationship between genetic polymorphism and external apical root resorption., Methodology: The protocol was prepared and registered on PROSPERO. Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliographies of all relevant articles and textbooks were manually searched., Results: Thirteen studies met the inclusion criteria. Four studies were classified as low-quality studies (score <10), and nine studies were classified as high-quality studies., Discussion: The results of the present review suggest that, although some authors have reported that genetic polymorphism may play a role in external apical root resorption, others have not supported this association. Future studies should be more consistent in their research methodologies to determine with clarity whether an association exists., Conclusion: Future investigations should include larger sample sizes with matching cases/controls, adjust for confounders, provide power calculation and odds ratios, and report genetic analyses with the Hardy-Weinberg equilibrium. The current investigation suggests guidelines and recommendations for future investigators studying genetic polymorphism in patients undergoing orthodontic treatment.

Introduction: Recent studies indicate that the osteoprotegerin (OPG)/RANKL/RANK pathway takes part in root resorption. However, the relationship between OPG and root resorption is vague. The purpose of our study was to investigate the role of OPG in root resorption., Methods: The first molars of the mandibles of osteoprotegerin-knockout (Opg-KO) mice and wild-type (WT) mice were evaluated by micro-computed tomography, histology, and immunohistochemistry at 4, 6, 26, and 52 weeks. To detect the activity of the osteoclasts, we induced bone marrow macrophages into osteoclast-like cells from Opg-KO mice and wild-type mice in vitro and then compared their osteoclast activities. To evaluate the cementum quality, an osteoclast-cementum co-culture model was established in vitro., Results: In Opg-KO mice, root resorption began at the age of 4 weeks. At 6 weeks the cementum damage extended to the coronal and apical regions, and at 52 weeks the damage reached the predentin. At all observed stages, more tartrate-resistant acid phosphatase (TRAP)-positive cells were found on the surface of cementum in Opg-KO mice. In vitro, the mRNA levels of cathepsin K, TRAP, matrix metalloproteinase-9, and matrix metalloproteinase-1, as well as the protein expression of nuclear factor of activated T cell 1 and TRAP, increased significantly in osteoclast-like cells from Opg-KO mice. In addition, the cementum resorption pits of Opg-KO mice were larger when co-cultured with osteoclast-like cells., Conclusions: Our study demonstrated that loss of OPG led to root resorption via increasing activation of osteoclasts and reducing mineralization of cementum., (Copyright © 2016. Published by Elsevier Inc.)

Objective: Interleukin-1 beta (IL1B) pathway is a key player in orthodontic-induced external apical root resorption (EARR). The aim of this work was to identify the genes related to the IL1 pathway as possible candidate genes for EARR, which might be included in an integrative predictive model of this complex phenotype., Materials and Methods: Using a stepwise multiple linear regression model, 195 patients who had undergone orthodontic treatment were assessed for clinical and genetic factors associated with %EARRmax (maximum %EARR value obtained for each patient). The four maxillary incisors and the two maxillary canines were assessed. Three functional single nucleotide polymorphisms (SNPs) were genotyped: rs1143634 in IL1B gene, rs315952 in IL1RN gene, and rs1059703 in X-linked IRAK1 gene., Results: The model showed that four of the nine clinical variables and one SNP explained 30% of the %EARRmax variability. The most significant unique contributions to the model were gender (P = 0.001), treatment duration (P < 0.001), premolar extractions (P = 0.003), Hyrax appliance (P < 0.001), and homozygosity/hemizygosity for variant C from IRAK1 gene (P = 0.018), which proved to be a protective factor., Conclusion: IRAK1 polymorphism is proposed as a protective variant for EARR., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: External apical root resorption (EARR) is a common complication in orthodontic treatment. Despite many studies on EARR, great controversies remain with regard to its risk factors. The objective of this study was to explore the relationship among sex, root movement, IL-1RN single nucleotide polymorphism (SNP) rs419598, IL-6 SNP rs1800796, and EARR associated with orthodontic treatment., Methods: Altogether 174 patients (with 174 maxillary left central incisors) were selected for this study. Cone-beam computed tomography was performed before the start of the treatment and at the end of the treatment. Cone-beam computed tomography data were used to reconstruct a 3-dimensional image of each tooth; the volume and the root resorption volume of each tooth were calculated. Three-dimensional matching was used to measure the amount of movement of each root. Genomic DNA was extracted from buccal swabs, and genotypes of SNP rs419598 and SNP rs1800796 of each subject were determined using TaqMan polymerase chain reaction genotyping (Applied Biosystems, Foster City, Calif). The data were analyzed with multiple linear regression analysis., Results: The statistical analysis indicated no relationship between sex, tooth movement amount, and IL-1RN SNP rs419598 with EARR. The IL-6 SNP rs1800796 GC was associated with EARR, and root resorption differed significantly between SNP rs1800796 GC and CC., Conclusions: IL-6 SNP rs1800796 GC is a risk factor for EARR. The amount of root movement, IL-1RN SNP rs419598, and sex as risk factors for EARR need further study., (Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate whether single nucleotide polymorphisms (SNPs) within the interleukin-1 gene cluster (IL1) are associated with the occurrence and severity of inflammatory external root resorption (IERR) after replantation of avulsed permanent teeth., Methodology: Indexes of IERR were radiographically assessed in 182 mature replanted permanent teeth from 146 patients at the onset of endodontic therapy. DNA was extracted from buccal mucosa cells and genotyped using TaqMan probes-based assays for the SNPs IL1A -889C/T (rs 180058), IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598). Teeth were grouped into two categories: IERR absent to mild (indexes ≤ 4) and moderate to severe IERR (indexes > 4). Genetic variations in the IL1 gene cluster were tested for their effect on the occurrence and extension of IERR using the GEE model (generalized estimation equation). Patient's age at the moment of injury, timing of pulpectomy, extra-alveolar period and storage condition of the avulsed teeth was included as possible confounders., Results: No association was found between SNPs IL1A -889C/T, IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598) and IERR indexes. Timing of pulpectomy (OR 3.5 IC 95% 2.0-6.2 P < 0.001) and patient's age at the moment of trauma (OR 0.29 IC 95% 0.12-0.67 P = 0.004) significantly affected the risk of developing severe IERR., Conclusions: While timing of pulpectomy and patient's age at the moment of trauma were confirmed as important risk factors, SNPs within the IL1 gene cluster did not affect the susceptibility for IERR after replantation of permanent teeth., (© 2014 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Objective: As genetic variation accounts for two-thirds of the variation in external apical root resorption (EARR) concurrent with orthodontic treatment, we analyzed the association of selected genetic and treatment-related factors with EARR concurrent with orthodontic treatment., Setting and Sample Population: This case-control study of 134 unrelated, orthodontically treated Caucasian individuals was conducted in part at an Indiana Private Practice, Indiana University and the University of Kentucky., Methods: Utilizing a research data bank containing information from ~1450 orthodontically treated patients, pre- and post-treatment radiographs from 460 individuals were evaluated for EARR of the four permanent maxillary incisors. Sixty-seven unrelated Caucasians with moderate to severe EARR were identified and were age-/sex-matched with orthodontically treated Caucasian controls yielding 38 females and 29 males per group. Factors tested for an association with EARR included the following: 1) treatment duration, 2) extraction of maxillary premolars, 3) numerous cephalometric measurements, and 4) DNA polymorphisms within/near candidate genes in a pathway previously implicated in EARR such as the purinergic-receptor-P2X, ligand-gated ion channel 7 (P2RX7; rs208294, rs1718119, and rs2230912), caspase-1 (CASP1; rs530537, rs580253, and rs554344), interleukin-1 beta (IL1B; rs1143634), interleukin-1 alpha (IL1A; rs1800587), and interleukin-1 receptor antagonist (IL1RA; rs419598) genes. Stepwise logistic regression was utilized to identify the factors significantly associated (significance taken at or less than the layered Bonferroni correction alpha) with the occurrence of EARR., Results: A long length of treatment and the presence of specific genotypes for P2RX7 SNP rs208294 were significantly associated with EARR., Conclusion: EARR occurrence was associated with both genetic and treatment-related variables, which together explained 25% of the total variation associated with EARR in the sample tested., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: There are multiple causes of external root resorption, but absent a disease state, it is most often observed when excessive physical force is used during orthodontic treatment. Even without mechanical stimulation, however, root resorption can still occur. The purpose of this study was to test whether Wnt signaling plays a role in pathologic root resorption, by conditionally deleting Wntless (Wls) from odontoblasts and osteoblasts and then evaluating the phenotypic effects on the maintenance of the root surface., Methods: Ten (age, 1 month) and 20 (age, 3 months) OCN-Cre;Wls(fl/fl) mice and their wild-type littermates were evaluated using microcomputed tomography, histology, and immunohistochemistry. Phenotypic alterations in the alveolar bone, dentin, and cementum were characterized and quantified., Results: In a genetic model of reduced Wnt signaling, we found that RANKL expression is upregulated, and osteoprotegerin expression is downregulated. This molecular disruption results in an increase in osteoclast activity, a decrease in osteoblast activity, and extensive, spontaneous root resorption. A genetic strain of mice in which Wnt signaling is elevated exhibits thicker cementum, whereas, even in the perinatal period, OCN-Cre;Wls(fl/fl) mice exhibit thinner cementum., Conclusions: Taken together, these data demonstrate that Wnts regulate cementum homeostasis, and that idiopathic cases of root resorption might have as their etiology a reduction in endogenous Wnt signaling., (Copyright © 2014 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Objective: External apical root resorption (EARR) is a frequent iatrogenic effect of orthodontic treatment. Substantial variability in responses to postorthodontic EARR has been observed among patients even when similar treatment protocols were used. This observation suggests that environmental and/or genetic variations between individuals may confer susceptibility or resistance to developing EARR. The objective of this study is to determine whether variants in the osteopontin gene, an essential mediator in the odontoclast fusion and attachment process, are positively/negatively associated with postorthodontic EARR., Materials and Methods: Genetic screening of eighty-seven orthodontic patients was performed for two polymorphisms in the osteopontin gene cluster (rs9138 and rs11730582). Subjects were divided into groups, according to the presence or absence of EARR (>2 mm). Genotype distributions and allelic frequencies were calculated using the chi-square test. Logistic regression analysis was used to assess the extent to which clinical-related parameters interfered with the EARR. Odds ratios (OR) and 95% confidence intervals were also calculated., Results: Data from this study show that subjects heterozygous and homozygous for the most frequent allele of the osteopontin gene at position 89261521 [OR: 0.035 (P = 0.035*) (allele A)] and 89253600 [OR: 0.20 (P = 0.025*) (allele T)], respectively, are protected against postorthodontic EARR. Nevertheless, a highly significant association was found in the comparative analysis of homozygous subjects [2/2 (CC)] for the osteopontin gene (rs9138), resulting in an increased risk of suffering postorthodontic EARR[OR: 4.10; P = 0.045*; CI: 95%]. Subjects who were homozygous [2/2 (CC)] for the osteopontin gene (rs11730582) were more likely, and to a greater extent, to be affected with EARR [OR: 11.68; P < 0.039*; CI: 95%] compared with other genotypes., Conclusion: Variations in the osteopontin gene (rs9138 and rs11730582) are determinants of a genetic predisposition to suffer EARR secondary to orthodontic treatment., (© 2013 John Wiley & Sons A/S.)

The purpose of this meta-analysis was to determine whether genetic variants of the interleukin-1β[+3954 C>T (rs1143634)] (IL-1β +3954 C>T) gene polymorphisms were associated with orthodontic external apical root resorption (EARR). A meta-analysis was carried out using data entered into the PubMed and Embase electronic databases before October 5, 2012. A total of 7 studies were identified for meta-analysis. The strength of the relationship between IL-1β +3954 C>T polymorphism and the risk of EARR was assessed using odds ratio (OR). The studies provided overall OR estimates for EARR. Overall, the variant genotypes (CC and CT) of the IL-1β +3954 C>T polymorphism were unassociated with EARR risk compared with the TT homozygote [CC vs TT, OR = 1.28, 95% confidence interval (95%CI) = 0.27-6.08; CT vs TT, OR = 0.74, 95%CI = 0.11-5.02]. Similarly, no associations were found in the dominant and recessive models (dominant model, OR = 1.08, 95%CI = 0.24-4.86; recessive model, OR = 1.85, 95%CI = 0.87-3.93). No publication bias was found, and no association was apparent between the IL-1β +3954 C>T polymorphism and risk of EARR in orthodontic treatment patients. Further multicenter and better-controlled studies are required to confirm these findings.

External apical root resorption (EARR) is a frequent iatrogenic problem following orthodontic treatment in endodontically-treated teeth, about which the literature reports substantial variability in post-orthodontic treatment EARR responses. The main focus of the present study is to clarify whether variants in the interleukin-1 receptor antagonist gene coding for the IL-1ra protein have a positive/negative influence on EARR of endodontically-treated teeth. Ninety-three orthodontic patients were genetically screened for a single nucleotide polymorphism (SNP:rs419598) in the IL1 cluster. The sample was classified into 2 groups: group 1 (affected-group) showed radiographic EARR of more than 2mm; group 2 (control-group), had no EARR or EARR ≤ to 2mm following orthodontic treatment on root-filled teeth. Logistic regression analysis was performed to obtain an adjusted estimate between the SNPs studied and EARR. Genotype distributions, allelic frequencies, adjusted odds ratios (OR) and 95% confidence intervals were also calculated. We found that subjects homozygous [1/1(TT)] for the IL1RN gene [OR:10.85; p=0.001;CI:95%] were at risk of EARR in root-filled teeth. Genetic variants in the antagonist axis balance of the IL1RN (rs419598) have a direct repercussion on the predisposition to post-orthodontic EARR in root-filled teeth. Variants in allele 1 of the interleukin-1 receptor antagonist gene(rs419598) are associated(p=0.001**) with an increased risk of suffering post-orthodontic EARR in root-filled teeth.

Objective: External apical root resorption (EARR) is permanent shortening of the end of the tooth root. It is a common clinical complication of orthodontic treatment. Polymorphisms in the interleukin 1 (IL1) gene cluster have been related to an increased EARR risk. The aim of this study was to analyze possible associations of IL1 gene variants with EARR in Czech population., Subjects and Methods: In this case-control study, 32 patients with EARR (age 15.0 ± 4.1 years) and 74 controls (age 15.2 ± 5.3 years) were genotyped using PCR-based methods for IL1A (-889C/T), IL1B (+3953C/T), and IL1RN [IL1 receptor antagonist, variable number tandem repeat (VNTR)] gene polymorphisms., Results: While no statistical significant differences in the IL1A and IL1B genotype, allele and reconstructed IL1 haplotype frequencies between patients with EARR and controls were found, marginally significant differences were observed in the frequencies of IL1RN variant (P = 0.05 for *22 genotype and P = 0.06 for a short (2) allele). In addition, significant associations between IL1RN*12, *22 genotypes and the short (2) allele and EARR were identified in the subgroup of girls (P = 0.04 and P = 0.02, P = 0.02)., Conclusions: Although no significant role of IL1A (-889C/T) and IL1B (+3953C/T) variants in EARR was confirmed, IL1RN VNTR may be associated with EARR, especially in girls., (© 2012 John Wiley & Sons A/S.)

Aim: To investigate whether the genetic variants of the interleukin-1 gene cluster (IL1) are associated with a possible genetically induced variability in post-orthodontic external apical root resorption (EARR) in root filled teeth and their control counterparts with vital pulps., Methodology: One hundred and forty-six maxillary premolars were evaluated radiographically following orthodontic treatment. Genetic screening was performed on orthodontic patients for two single-nucleotide polymorphisms (SNPs: rs1800587 and rs1143634) in the IL1 gene cluster. Subjects were divided into two groups according to the presence or absence of radiographic post-orthodontic EARR (>2 mm) in root filled teeth and their controls with vital pulps. Logistic regression analysis was performed to obtain an adjusted estimation between EARR and IL1 polymorphisms. Allelic frequencies, genotype distributions, and adjusted odds ratio (OR), at 95% confidence interval, were also calculated., Results: Whilst no clear statistical association was found for gene variations in IL1A, a sound association was found in the comparative analysis of subjects homozygous [2/2(TT)] for the IL1B gene, which resulted in a two times increased risk of suffering post-orthodontic EARR in root filled teeth [OR, 2.032 (P = 0.031); CI,1.99-14.77] when compared with their controls with vital pulps. There was, however, a shared predisposition to EARR in controls with vital pulps and root filled teeth of subjects homozygous for allele 1 [OR, 5.05 (P = 0.002)] and [OR, 2.77 (P = 0.037)], respectively., Conclusions: Genetic variations in the interleukin-1β gene (rs1143634) predispose root filled teeth to EARR for matched pairs secondary to orthodontic treatment in a different way from their control teeth with vital pulps in subjects homozygous for allele 2 [2/2(TT)]., (© 2012 International Endodontic Journal.)

Introduction: Vitamin D is responsible for the regulation of certain genes at the transcription level, via interaction with the vitamin D receptor, and influences host immune responses and aspects of bone development, growth, and homeostasis. Our aim was to investigate the association of TaqI vitamin D receptor gene polymorphism with external apical root resorption during orthodontic treatment., Methods: Our subjects were 377 patients with Class II Division 1 malocclusion, divided into 3 groups: (1) 160 with external apical root resorption ≤1.43 mm, (2) 179 with external apical root resorption >1.43 mm), and (3) 38 untreated subjects. External apical root resorption of the maxillary incisors was evaluated on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, vitamin D receptor TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables with external apical root resorption (P <0.05)., Results: There was a higher proportion of external apical root resorption in orthodontically treated patients compared with the untreated subjects. In patients orthodontically treated, age higher than 14 years old, initial size of the maxillary incisor root superior to 30 mm, and premolar extraction were associated with increased external apical root resorption. Genotypes containing the C allele were weakly associated with protection against external apical root resorption (CC + CT × TT [odds ratio, 0.29; 95% confidence interval, 0.07-1.23; P = 0.091]) when treated orthodontic patients were compared to untreated individuals., Conclusions: Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients., (Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Objective: External apical root resorption (EARR) is a frequent iatrogenic effect of orthodontic treatment. Patients with genetic variants in the interleukin 1 gene have been related to an increased risk of suffering EARR. The objective of this study is to determine whether variants in the interleukin 1 receptor antagonist gene are positively/negatively associated with interleukin 1 gene polymorphisms, particularly in relation to the clinical features of EARR patients., Materials and Methods: Genetic screening of 54 orthodontic patients was performed for three polymorphisms (rs1800587, rs1143634 and rs419598) in the IL1 gene cluster. Subjects were divided according to the presence or absence of EARR of more than 2 mm. The genotype distributions and allelic frequencies were calculated by the chi-square-test. Odds ratios (OR) and 95% confidence intervals were also calculated., Results: A highly significant association was found in the comparative analysis of homozygous subjects [1/1(CC)] for the IL1B gene, resulting in an increased risk of suffering postorthodontic EARR (OR: 3.47; P = 0.027; CI: 95%). While no association was found for the IL1A gene (P = 0.097), subjects who were homozygous [1/1(TT)] for the IL1RN gene were more likely to be affected with EARR (OR: 6.75; P = 0.001; CI: 95%)., Conclusion: Variations in the interleukin 1 receptor antagonist gene (rs419598) - and not only in the IL1B gene (rs1800587) - are determinants of a predisposition to postorthodontic EARR., (© 2011 John Wiley & Sons A/S.)