TRPV4 mediates macrophage polarization involved in inflammatory root resorption induced by mechanical pressure

Background Orthodontically induced inflammatory root resorption (OIIRR) is unwelcome iatrogenic damage associated with orthodontic treatment. Patients with a high risk of developing OIIRR are commonly monitored using radiographic techniques. Alternative, more sensitive methods using biological markers facilitate the early detection of OIIRR, which can minimise root surface damage and allow the timely cessation of orthodontic treatment in order to facilitate a reparative process. Aim The present review examines the current use of 2D and 3D radiographic techniques to detect and quantify OIIRR and, further, evaluates the latest literature on alternative detection methods of OIIRR. Method Published studies were searched electronically throughout PubMed, Scopus and ScienceDirect using keywords including ‘root resorption’, ‘OIIRR’, ‘radiograph’ and ‘biological markers’. Results The detection methods for OIIRR were divided into radiographic and biological marker methods. Orthopantomogram (OPG) and periapical radiography are currently the most widely used radiographic methods to detect and monitor OIIRR as they are readily available in most dental clinics, cost effective and have a relatively low radiation dose. However, the radiographic methods are not only subject to standardisation and magnification issues, but also require repeated radiation exposure to patients. Therefore, published research into the potential for biological markers as a safer and more sensitive alternative for the early detection of OIIRR was reviewed. Conclusion The result of the review highlights the potential for the use of biological markers in the early detection of OIIRR as a relatively safer and more sensitive alternative to conventional radiographic methods.

Orthodontically induced inflammatory root resorption (OIIRR) is one of the most severe and common complications associated with clinical orthodontic treatment. With the widespread application of new technologies such as cone-beam computed tomography in clinical dental practice, a significant number of root resorption cases have been detected. Therefore, it is particularly important to effectively avoid and control root resorption during clinical treatment. However, the specific molecular biological mechanisms underlying OIIRR have not been fully elucidated, and there are currently no effective therapeutic approaches. It is essential to investigate the mechanisms by which orthodontic pressure acts on periodontal tissue cells, disrupts root homeostasis, and triggers OIIRR, as well as to explore experimental treatment strategies. This review summarizes the pathophysiological cascade leading to OIIRR, organizes emerging mechanisms (such as classical pyroptosis of periodontal tissue cells, ferroptosis of periodontal ligament stem cells, and the sensing role of mechanosensitive channels in response to orthodontic pressure), and outlines current experimental treatment strategies for OIIRR.

Root resorption can be considered the most unfortunate complication of orthodontic treatment. To evaluate the available evidence regarding orthodontically induced inflammatory root resorption (OIIRR). A comprehensive literature search was conducted for the systematic reviews investigating OIIRR published up to 24 May 2020. This was accomplished using electronic databases: MEDLINE via OVID, EMBASE, AMED (Allied and Complementary Medicine Database), PubMed, and Web of Science. Any ongoing systematic reviews were searched using Prospero and a grey literature search was undertaken using Google Scholar and OpenGrey (www.opengrey.eu/). No language restriction was applied. Only studies investigating OIIRR were included. Screening, quality assessment [using the AMSTAR 2 tool (A Measurement Tool to Assess Systematic Reviews)], and data extraction were performed by two authors independently. Information was categorized and narratively synthesized for the key findings from moderate and high-quality reviews. A total of 2033 potentially eligible studies were identified. After excluding the non-relevant studies, 28 systematic reviews were included. Of which, 20 systematic reviews (71.5%) were of moderate and high-quality level of evidence. The incidence and severity of OIIRR increase with the fixed appliance, especially with heavy force, intrusion, torqueing movements, increased treatment duration, and treatment with extractions or with long apical displacement (particularly for maxillary incisors). There was insufficient evidence regarding most other treatment- and patient-related factors on OIIRR. Following all precautionary measures, pausing treatment and regular monitoring benefits patients with OIIRR. There is a limited number of high-quality studies in terms of OIIRR. The influence of fixed appliance on root resorption was noted; however, the cause and effect relationship between OIIRR and orthodontic biomechanics has not been confirmed. Avoiding heavy, continuous forces and a greater amount of apical displacement over a long duration of treatment is recommended. Precautionary measures should be carefully considered when treating patients with a high risk of OIIRR. CRD42020166629.

Residents' journal review

Orthodontically induced inflammatory root resorption (OIIRR) is a common adverse effect of orthodontic treatments. Radiographs are routinely used to diagnose OIIRR; however, 3-dimensional cone beam computed tomography (CBCT) studies have recently been conducted to assess hard tissue loss more accurately. There is controversial evidence of differences between aligners and fixed appliances in terms of OIIRR. This meta-analysis aims to investigate the differences in OIIRR between fixed appliances and aligners based on recent CBCT-based studies. A systematic review and meta-analysis was conducted after PROSPERO registration. Four databases (MEDLINE, Embase, CENTRAL, Scopus) were systematically screened to identify studies reporting on (P) patients with full permanent dentition treated with (I) aligners or (C) fixed orthodontic appliances that reported on (O) root resorption detected by CBCT, without any date or language restrictions. Exclusion criteria included incomplete dentition, root canal treatment, dental trauma, previous root resorption, and developmental abnormalities. Means and mean differences were used as effect size measures, Chi-squared tests for subgroup differences, and I2 values for heterogeneity were calculated. Risk of bias was evaluated using ROBINS-I and RoB2 tools. The meta-analysis included five studies with 334 participants. Data on upper incisors were sufficient for analysis. Differences in OIIRR between aligners and fixed appliances did not reach statistical significance (p > 0.05), and neither group presented clinically relevant OIIRR (< 1mm). A moderate to high risk of bias was present. All treatment modalities caused similar, clinically irrelevant levels of OIIRR in the investigated population. The treatment modality should be selected based on biomechanics, expected outcomes, and individual preferences. Clinicians should not prioritize aligners over fixed appliances in the non-risk population in fear of OIIRR. The results should be interpreted cautiously due to the risk of bias and heterogeneity. PROSPERO: CRD42023481411.

BackgroundThis review synthesizes the available evidence about the predisposition of individuals with asthma or allergies to orthodontically induced inflammatory root resorption (OIIRR) and possible factors related to root resorption that were investigated in the included studies, such as the type of malocclusion, duration of orthodontic treatment, and tooth units.Material and methodsSix electronic databases and partial gray literature were searched without date or language restrictions until September 2020. Prospective and retrospective observational cohort and case-control studies were included. The risk of bias (RoB) was assessed using the checklists from the Joanna Briggs Institute and the certainty of the evidence using the GRADE tool. To complement the case-control studies, the odds ratio (OR) of the individuals with allergies/asthma to develop root resorption was calculated.ResultsSix studies were included. One study with low RoB, one with moderate, and one with high RoB stated that allergic patients did not report a greater chance of developing OIIRR (OR = 1.17 to 2.10, p = 0.1 to 1), while only one study with low RoB reported that individuals with allergies tend to develop root resorption (OR = 2.4, 95% CI = 1.08-5.37). Three studies with low RoB and one with moderate showed no significant association between asthma and OIIRR (OR = 1.05 to 3.42, p = 0.12 to 0.94). No association was identified between the type of malocclusion and the degree of OIIRR. Uniradicular dental units and a prolonged treatment time seem to be associated with an increased risk of resorption. The certainty of the evidence was considered low for both exposure factors.ConclusionEvidence with a low level of certainty indicates that individuals with allergies or asthma are not more predisposed to OIIRR. Uniradicular teeth and long-term orthodontic treatments are associated with a higher risk of OIIRR.Systematic review registrationPROSPERO CRD42020188463

Biologic factors and adjunctive therapies are known to affect the degree of orthodontically induced inflammatory root resorption (OIIRR). However, a systematic overall assessment of their impact on OIIRR has not previously been reported. We, therefore, aimed to systematically assess effects on OIIRR of biologic factors and adjunctive therapies in human and animal subjects. A comprehensive search strategy was performed for all major electronic databases. Two reviewers independently selected studies, undertook data extraction and assessed the risk of bias for all included studies according to a pre-specified protocol inspired by Cochrane and the PRISMA guidelines. Eligible studies compared the effect of intervention(s) in an experimental and a control group. A total of 9 human and 36 animal trials met the inclusion criteria. Where appropriate, random-effect meta-analyses were carried out to determine the outcome measure OIIRR. The random-effect meta-analysis demonstrated that OIIRR was inhibited by fluoride (ES = -2.08 [-3.02, -1.14]), thyroxine (ES = -1.91 [-3.20, -0.61]), and steroids (ES = -2.79 [-4.26, -1.33]). In contrast, corticotomy (ES = 0.38 [0.05, 0.71]) significantly enhanced OIIRR. In animals, administration of fluoride, thyroxine and steroids decreased OIIRR, whereas corticotomy increased OIIRR. In general, the effect on OIIRR increased with higher dosage and/or exposure time. Despite methodological limitations of the included studies, this systematic review provides an important overview of the effect of biologic factors and adjunctive therapies on OIIRR.

Orthodontically induced inflammatory root resorption (OIIRR) is an inflammation induced by excessive orthodontic force in the periodontium. The aim of this study was to identify the role of ferroptosis in periodontal ligament cells in OIIRR and its underlying mechanism. Human periodontal ligament cells (hPDLCs) were subjected to 2 g/cm2 of compressive stress along with 20 ng/mL of interleukin-1β (IL-1β) stimulation for 24 h. The occurrence of ferroptosis in hPDLCs is detected by Western blot analysis and ferroptosis-related kits. For invivo analyses, a mouse OIIRR model was established, and the ACSL4 inhibitor (Rosiglitazone, Rosi) was administered intraperitoneally. Micro-CT was employed to evaluate the occurrence of OIIRR, and immunohistochemical staining (IHC) was performed to detect changes in ferroptosis-related markers. Upon applying compressive stress and IL-1β stimulation to hPDLCs, Western blot analysis showed an upregulation of the ferroptosis marker ACSL4 and a downregulation of GPX4, along with significant increases in ROS, MDA and Fe2+ levels, indicating enhanced ferroptosis. However, when hPDLCs were treated with Rosi (1 μM), ferroptosis was alleviated. Micro-CT analysis showed that root resorption volume decreased after Rosi application. Additionally, Ferroptosis-related markers changed significantly in the PDLCs in mice via IHC staining. ACSL4-mediated ferroptosis, triggered by compressive stress and inflammation in hPDLCs, contributed to the development of OIIRR. Rosi has been shown to inhibit OIIRR and serve as a novel therapeutic target for OIIRR treatment.

Orthodontically induced inflammatory root resorption (OIIRR) poses a significant clinical challenge, as excessive orthodontic force shortens tooth longevity by impairing cementoblast-mediated cementum mineralization and promoting root resorption. Cementoblasts, essential for mineralized cementum formation and resistance to resorption, exhibit altered mechanosensitivity and mechanotransduction under orthodontic force, yet the role of mitophagy in this process remains poorly understood. In this study, we investigated how the S1PR1/mitophagy axis modulates cementoblast mineralization and OIIRR progression. The invivo orthodontic loading model revealed that heavy compression force triggered OIIRR and impaired cementoblast mineralization along with suppression of mitophagy in cementoblasts by downregulating PINK1 and PARKIN expression. The invitro experiments further confirmed that heavy compression force increased reactive oxygen species (ROS) levels, disrupted mitochondrial membrane potential (MMP), and inhibited mitophagy in OCCM30 cells, thereby impairing their mineralization capacity. Mechanistically, S1PR1 upregulation activated mitophagy, which in turn restored cementoblast mineralization under heavy compression force. Moreover, pharmacological activation of S1PR1 with SEW2871 alleviated OIIRR invivo. These findings highlight the pivotal role of the S1PR1/mitophagy axis in maintaining cementoblast function and mineralization under orthodontic force, offering novel insights into the molecular mechanisms underlying OIIRR and suggesting potential therapeutic strategies to prevent OIIRR during orthodontic treatment.

SummaryBackgroundThe application of orthodontic forces causes root resorption of variable severity with potentially severe clinical ramifications.ObjectiveTo systematically review reports on the pathophysiological mechanisms of orthodontically induced inflammatory root resorption (OIIRR) and the associated risk factors based on in vitro, experimental, and in vivo studies.Search methodsWe undertook an electronic search of four databases and a separate hand-search.Selection criteriaStudies reporting on the effect of orthodontic forces with/without the addition of potential risk factors on OIIRR, including (1) gene expression in in-vitro studies, the incidence root resorption in (2) animal studies, and (3) human studies.Data collection and analysisPotential hits underwent a two-step selection, data extraction, quality assessment, and systematic appraisal performed by duplicate examiners.ResultsOne hundred and eighteen articles met the eligibility criteria. Studies varied considerably in methodology, reporting of results, and variable risk of bias judgements.In summary, the variable evidence identified supports the notion that the application of orthodontic forces leads to (1) characteristic alterations of molecular expression profiles in vitro, (2) an increased rate of OIIRR in animal models, as well as (3) in human studies. Importantly, the additional presence of risk factors such as malocclusion, previous trauma, and medications like corticosteroids increased the severity of OIIRR, whilst other factors decreased its severity, including oral contraceptives, baicalin, and high caffeine.ConclusionsBased on the systematically reviewed evidence, OIIRR seems to be an inevitable consequence of the application of orthodontic forces—with different risk factors modifying its severity. Our review has identified several molecular mechanisms that can help explain this link between orthodontic forces and OIIRR. Nevertheless, it must be noted that the available eligible literature was in part significantly confounded by bias and was characterized by substantial methodological heterogeneity, suggesting that the results of this systematic review should be interpreted with caution.RegistrationPROSPERO (CRD42021243431).

HDAC9-Mediated Pyroptosis Promotes Orthodontically Induced Inflammatory Root Resorption.

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

Orthodontic treatment commonly results in orthodontically induced inflammatory root resorption (OIIRR). This condition arises from excessive orthodontic force, which triggerslocal inflammatory responses and impedes cementoblasts' mineralization capacity. Low-intensity pulsed ultrasound (LIPUS) shows potential in reducing OIIRR. However, the precise mechanisms through which LIPUS reduces OIIRR remain unclear. This study aimed to explore the effects and mechanisms of LIPUS on the mineralization of force-treated cementoblasts and its impact on OIIRR. We established a rat OIIRR model and locally administered LIPUS stimulation for 7 and 14 days. We analyzed root resorption volume, osteoclast differentiation, and the expression of osteocalcin and yes-associated protein 1 (YAP1) using micro-computed tomography (micro-CT), hematoxylin and eosin, tartrate-resistant acid phosphatase, immunofluorescence and immunohistochemistry staining. Invitro, we applied compressive force and LIPUS to the immortalized mouse cementoblasts (OCCM30). We assessed mineralization using alkaline phosphatase (ALP) staining, alizarin red staining, real-time quantitative polymerase chain reaction, Western blotting and immunofluorescence staining. In rats, LIPUS reduced OIIRR, as evidenced by micro-CT analysis and histological staining. Invitro, LIPUS enhanced mineralization of force-treated OCCM30 cells, as indicated by ALP and alizarin red staining, upregulated mRNA expression of mineralization-related genes, and increased protein expression of mineralization markers. Mechanistically, LIPUS activated YAP1 signaling via the cytoskeleton-Lamin A/C pathway, supported by immunofluorescence and Western blot analysis. This study demonstrates that LIPUS promotes mineralization in force-treated cementoblasts and reduces OIIRR by activating YAP1 through the cytoskeletal-Lamin A/C signaling pathway. These findings provide fresh insights into how LIPUS benefits orthodontic treatment and suggest potential strategies for preventing and treating OIIRR.

Ultrasound is an effective tool for both diagnostic and therapeutic applications. As an imaging tool, ultrasound has mostly been used for real-time noninvasive diagnostic imaging. As ultrasound propagates through a material, a reflected radio-frequency (RF) signal is generated when encountering a mismatch in acoustic impedance. While traditionally recognized for its diagnostic imaging capabilities, the application of ultrasound has broadened to encompass therapeutic interventions, most notably in the form of Low-Intensity Pulsed Ultrasound (LIPUS). Low-Intensity Pulsed Ultrasound (LIPUS) is a form of mechanical energy transmitted transcutaneously by high-frequency acoustic pressure waves. The intensity of LIPUS (30 mW/cm2) is within the range of ultrasound intensities used for diagnostic purposes (1–50 mW/cm2) and is regarded as non-thermal, non-destructive, permeating living tissues and triggering a cascade of biochemical responses at the cellular level. The LIPUS device produces a 200 µs burst of 1.5 MHz acoustic sine waves, that repeats at a modulation frequency of 1 kHz and provides a peak pressure of 30 mW/cm2. Low-intensity pulsed ultrasound (LIPUS) forms one of the currently available non-invasive healing-enhancing devices besides electro-stimulation (pulsed electro-magnetic field, PEMF). This modality has been leveraged to enhance drug delivery, expedite injury recovery, improve muscle mobility, alleviate joint stiffness and muscle pain, and enhance bone fracture healing. Although LIPUS has been embraced within various medical disciplines, its integration into standard dental practices is still in its nascent stages, signifying an unexplored frontier with potentially transformative implications. Low-intensity pulsed ultrasound (LIPUS) has emerged as an attractive adjuvant therapy in various dental procedures, such as orthodontic treatment and maxillary sinus augmentation. Its appeal lies in its simplicity and non-invasive nature, positioning LIPUS as a promising avenue for clinical innovation. One particular area of interest is orthodontically induced inflammatory root resorption (OIIRR), an oftenunavoidable outcome of the orthodontic intervention, resulting in the permanent loss of root structure. Notably, OIIRR is the second most common form of root resorption (RR), surpassed only by root resorption related to pulpal infection. Given the high prevalence and potential long-term consequences of OIIRR, this literature review seeks to evaluate the efficacy of LIPUS as a therapeutic approach, with an emphasis on assessing its capacity to reduce the severity of OIIRR to a level of clinical significance. To conduct this systematic review, a comprehensive automated literature search was executed across multiple databases, including MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, SciELO, Cochrane, PubMed, trials registries, 3ie, and Google Scholar. Both forward and backward citation tracking was employed, encompassing studies published from database inception through January 2009 to April 2023. The review focused on randomized controlled trials (RCTs) that specifically evaluated the effects of low-intensity pulsed ultrasound therapy on orthodontically induced inflammatory root resorption (OIIRR), without restrictions of publication date. A stringent selection criterion was applied, and only studies demonstrating high levels of statistical significance were included. Ultimately, fourteen studies met the inclusion criteria and were subjected to further analysis. The overall quality of the included randomized controlled trials (RCTs) was rigorously assessed utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. This analysis revealed certain methodological limitations that posed challenges in drawing definitive conclusions from the available evidence. Despite these constraints, the review offers invaluable insights that can inform and guide future research. Specifically, it delineates recommendations for targeted populations, necessary interventions, appropriate outcome measures, suitable study designs, and essential infrastructure to facilitate further investigations. The synthesis of these insights aims to enhance the development and application of low-intensity pulsed ultrasound therapy within the field of dentistry, thereby contributing to improved patient outcomes.

People, in increasing numbers, are seeking orthodontic treatment to correct malocclusion, while some of them are suffering from orthodontically induced inflammatory root resorption (OIIRR). Recent evidence suggests that the immune-inflammatory response occurring during bone remodeling may be responsible for OIIRR. Ferroptosis, a new type of programmed cell death (PCD), has been found to have a close interrelation with inflammation during disease progression. While ferroptosis has been extensively studied in bone-related diseases, its role in OIIRR is poorly understood. Considering that the tooth root shares a lot of similar characteristics with bone, it is reasonable to hypothesize that ferroptosis contributes to the development of OIIRR. Nevertheless, direct evidence supporting this theory is currently lacking. In this review, we introduced ferroptosis and elucidated the mechanisms underlying orthodontic tooth movement (OTM) and OIIRR, with a special focus on the pivotal role inflammation plays in these processes. Additionally, we covered recent research exploring the connections between inflammation and ferroptosis. Lastly, we emphasized the important regulatory function of ferroptosis in bone homeostasis. Further investigations are required to clarify the modulation mechanisms of ferroptosis in OIIRR and to develop novel and potential therapeutic strategies for the management of OIIRR.