Does aligner refinement have the same efficiency in deep bite correction?: A retrospective study.

BACKGROUND: Refinements are very common in clear aligner treatments. The aim of this study is to assess whether the predictability of deep overbite correction is similar over several refinements using clear aligners (Invisalign, Align Technology, San Jose, Calif) and examine the accuracy of vertical movement and inclination change of individual teeth. METHODS: This retrospective study included 20 deep bite patients (7M and 13F; 32.63 ± 11.88 years old; an initial overbite of 5.09 ± 0.98 mm), consecutively treated from September 2016 and March 2023, who completed at least two sets of aligners, including refinements. The initial, predicted, and achieved models were exported from ClinCheck or OrthoCAD (Cadent Inc, Carlstadt, NJ) and superimposed via best-fit surface-based registration using SlicerCMF (version 4.9.0; cmf.slicer.org). We also examined 15 out of 20 patients who completed treatments. The overbite correction and changes in vertical movement and inclination for individual teeth were measured. Descriptive statistics and a paired t-test or Wilcoxon signed-rank test were performed. P < 0.05 was considered statistically significant. RESULTS: The mean accuracy of overbite correction was 37.63% after 1st set, followed by 11.19%, 6.32%, and 13.80% (2nd-4th sets), respectively. There were statistically significant differences between the predicted and achieved vertical movements and inclination changes for all teeth for the 1st and 2nd sets. For the completed cases, the mean overbite correction was 38.54% compared to the initially planned overbite correction, which is similar to one of the 1st set. Still, the vertical movements and inclination changes of all teeth present statistically significant differences between the initially planned and finally achieved movements except for maxillary lateral incisor torque. CONCLUSIONS: The most overbite correction occurs during the 1st set of aligners, and refinement treatment does not significantly improve the deep bite correction.

Comparison of the skeletodental effects of miniscrew-anchored and tooth-anchored facemask treatment in growing patients with skeletal class III malocclusions.

INTRODUCTION: This retrospective study aimed to evaluate the skeletal and dental effects of the miniscrew-anchored facemask in skeletal Class III growing patients and compare them with those of conventional tooth-anchored facemasks. METHODS: Retrospectively a total of 50 patients with skeletal Class III (mean ANB: -1.12°) were investigated and divided into two groups according to the treatment modality. Twenty-five patients were treated using the conventional tooth-anchored facemask (T group: mean age 9.3 ± 1.1 years, mean ANB: -0.93°) whereas the other 25 were treated using a miniscrew-anchored facemask (M group: mean age 9.7 ± 1.3 years. mean ANB: -1.61°). Two miniscrews were placed on the palate for bone anchorage. In both T and M groups, facemasks applied a force of 20-30° down on the occlusal plane, and the force increased from 200 g to 300-350 g per side throughout the treatments. The patients were instructed to wear facemasks for at least 14 h per day. A total of 16 angular and 11 linear cephalometric measurements were analysed to determine the skeletal and dental changes before and after facemask treatment. A paired t-test was used to verify the effects before and after treatment in each group. RESULTS: All miniscrews were well maintained during treatment. The values of SNA, SN-ANS, ANB and A to N-Perp, which indicate anterior protraction of the maxilla, were significantly higher in the M group compared with the T group (P < .05). Proclination of the maxillary incisors, extrusion and mesialization of the maxillary molars were significantly greater in the T group (P < .05). CONCLUSIONS: Miniscrew-anchored facemask treatment increased the amount of maxillary protraction and reduced the dental side effects compared with conventional tooth-anchored facemask treatment in growing patients with skeletal Class III malocclusion.

Osteoimmunology in Periodontitis and Orthodontic Tooth Movement.

PURPOSE OF REVIEW: To review the role of the immune cells and their interaction with cells found in gingiva, periodontal ligament, and bone that leads to net bone loss in periodontitis or bone remodeling in orthodontic tooth movement. RECENT FINDINGS: Periodontal disease is one of the most common oral diseases causing inflammation in the soft and hard tissues of the periodontium and is initiated by bacteria that induce a host response. Although the innate and adaptive immune response function cooperatively to prevent bacterial dissemination, they also play a major role in gingival inflammation and destruction of the connective tissue, periodontal ligament, and alveolar bone characteristic of periodontitis. The inflammatory response is triggered by bacteria or their products that bind to pattern recognition receptors that induce transcription factor activity to stimulate cytokine and chemokine expression. Epithelial, fibroblast/stromal, and resident leukocytes play a key role in initiating the host response and contribute to periodontal disease. Single-cell RNA-seq (scRNA-seq) experiments have added new insight into the roles of various cell types in the response to bacterial challenge. This response is modified by systemic conditions such as diabetes and smoking. In contrast to periodontitis, orthodontic tooth movement (OTM) is a sterile inflammatory response induced by mechanical force. Orthodontic force application stimulates acute inflammatory responses in the periodontal ligament and alveolar bone stimulated by cytokines and chemokines that produce bone resorption on the compression side. On the tension side, orthodontic forces induce the production of osteogenic factors, stimulating new bone formation. A number of different cell types, cytokines, and signaling/pathways are involved in this complex process. Inflammatory and mechanical force-induced bone remodeling involves bone resorption and bone formation. The interaction of leukocytes with host stromal cells and osteoblastic cells plays a key role in both initiating the inflammatory events as well as inducing a cellular cascade that results in remodeling in orthodontic tooth movement or in tissue destruction in periodontitis.

Predictability of the deep overbite correction using clear aligners.

INTRODUCTION: The objective of this study was to investigate the predictability of overbite correction in patients with deepbite using the clear aligners (Invisalign, Align Technology, San Jose, Calif) and examine the accuracy of vertical movement and inclination change of individual teeth. METHODS: This retrospective study included 24 deepbite patients (10 males and 14 females; aged 32.8 ± 11.9 years; an initial overbite of 5.20 ± 0.95 mm; an average treatment period of 11.04 ± 4.14 months) consecutively treated from September 2016 and completed before August 2021. SmartTrack materials were used for all patients. The initial, predicted, and achieved final models were exported from ClinCheck and superimposed via best-fit surface-based registration using Slicer CMF (version 4.9.0; cmf.slicer.org). The overbite correction, changes in vertical movement, and inclination for individual teeth were measured. Descriptive statistics and a paired t test or Wilcoxon signed-rank test were performed. P <0.05 was considered statistically significant. RESULTS: Mean overbite correction was 33%, with a 1.15 mm improvement after the first set of aligners. All teeth demonstrated statistically significant differences between planned and achieved amounts in vertical movement and inclination change, with the largest difference in maxillary central incisors. Mandibular incisor intrusion and mandibular premolar extrusion had similar accuracies. Regarding inclination change, maxillary central incisors showed the lowest accuracy of 13.3%. CONCLUSIONS: Clear aligner treatment showed an average of 33% overbite correction. Overcorrection and additional refinement treatments are needed in most patients with a deepbite.

Correlation between TMJ Space Alteration and Disc Displacement: A Retrospective CBCT and MRI Study.

This study aims to determine if a large anterior and reduced posterior/superior joint space is highly predictable for disc displacement. From patients with temporomandibular disorders symptoms, fifty-two experimental joints and fourteen control joints were included. The cone beam computed tomography (CBCT) images were used to calculate posterior-to-anterior (P-A) and superior-to-anterior (S-A) joint space ratios, while disc position was determined using magnetic resonance imaging (MRI). One-way analysis of covariance test and receiver operating characteristics analysis were carried out. The results showed that among the 52 experimental joints, 45 were diagnosed as disc displacement and 7 as normal disc positions (N). All 14 control joints showed normal disc positions. The P-A ratio was 1.46 ± 0.21, 0.99 ± 0.23, and 0.86 ± 0.30 in the control, N, and DD groups, respectively (p < 0.001). The S-A ratio was 1.80 ± 0.27, 1.44 ± 0.33, and 1.08 ± 0.35 in the control, N, and DD groups, respectively (p < 0.001). When an altered P-A ratio and/or S-A ratio are observed on the CBCT, the diagnosis of disc displacement is quite predictable with high sensitivity and specificity.

The Effect of IFT80 Deficiency in Osteocytes on Orthodontic Loading-Induced and Physiologic Bone Remodeling: In Vivo Study.

Osteocytes are the main mechanosensory cells during orthodontic and physiologic bone remodeling. However, the question of how osteocytes transmit mechanical stimuli to biological responses remains largely unanswered. Intraflagellar transport (IFT) proteins are important for the formation and function of cilia, which are proposed to be mechanical sensors in osteocytes. In particular, IFT80 is highly expressed in mouse skulls and essential for ciliogenesis. This study aims to investigate the short- and long-term effects of IFT80 deletion in osteocytes on orthodontic bone remodeling and physiological bone remodeling in response to masticatory force. We examined 10-week-old experimental DMP1 CRE+.IFT80f/f and littermate control DMP1 CRE-.IFT80f/f mice. After 5 and 12 days of orthodontic force loading, the orthodontic tooth movement distance and bone parameters were evaluated using microCT. Osteoclast formation was assessed using TRAP-stained paraffin sections. The expression of sclerostin and RANKL was examined using immunofluorescence stain. We found that the deletion of IFT80 in osteocytes did not significantly impact either orthodontic or physiologic bone remodeling, as demonstrated by similar OTM distances, osteoclast numbers, bone volume fractions (bone volume/total volume), bone mineral densities, and the expressions of sclerostin and RANKL. Our findings suggest that there are other possible mechanosensory systems in osteocytes and anatomic limitations to cilia deflection in osteocytes in vivo.

Transverse Analysis of Maxilla and Mandible in Adults with Normal Occlusion: A Cone Beam Computed Tomography Study.

Objectives: To study the transverse widths of maxilla and mandible and their relationship with the inclination of first molars. Materials and Methods: Fifty-six untreated adults (12 males, 44 females) with normal occlusion were included. On each Cone Beam Computed Tomography (CBCT) image of the subject, inter-buccal and inter-lingual bone widths were measured at the levels of hard palate, alveolar crest and furcation of the first molars, and maxillomandibular width differentials were calculated. In addition, the buccolingual inclination of each first molar was measured and its correlation with the maxillomandibular width differential was tested. Results: At the furcation level of the first molar, the maxillary inter-buccal bone width was more than the mandibular inter-buccal bone width by 1.1 ± 4.5 mm for males and 1.6 ± 2.9 mm for females; the mandibular inter-lingual bone width was more than the maxillary inter-lingual bone width by 1.3 ± 3.6 mm for males and 0.3 ± 3.2 mm for females. For females, there was a negative correlation between the maxillomandibular inter-lingual bone differential and maxillary first molar buccal inclination (p < 0.05), and a positive correlation between the maxillomandibular inter-lingual bone differential and mandibular first molar lingual inclination (p < 0.05). Conclusions: This is a randomized clinical study on transverse analysis of maxilla and mandible in adults with normal occlusion using CBCTs. On average: (1) At the furcation level of the first molars, the maxillary inter-buccal bone width was slightly wider than mandibular inter-buccal bone width; whereas the mandibular inter-lingual bone width was slightly wider than maxillary inter-lingual bone width; (2) A statistically significant correlation existed between the maxillomandibular transverse skeletal differentials and molar inclinations.

Postoperative Changes in the Upper Airway Following Mandibular Distraction Osteogenesis in Pediatric Hemifacial Microsomia.

BACKGROUND: Patients with hemifacial microsomia (HFM) may undergo unilateral mandibular distraction osteogenesis (MDO) before skeletal maturity in an effort to improve facial symmetry. Mandibular distraction osteogenesis's effect on airway volumes have been studied in the past, though to our knowledge, none have accounted for the effect of head and neck posture on airway morphology. This study aimed to tackle this shortcoming, using imaging to analyze the upper airway of patients with HFM before and after surgical intervention with MDO. METHODS/DESCRIPTION: The authors retrospectively reviewed patients with a diagnosis of unilateral HFM whom underwent unilateral MDO with an oblique vector at age 4 to 14 years at a single institution from 2004 to 2019. Patients with pre- and post-MDO three-dimensional computed tomography scans of the upper airway within 12 months of distractor placement and removal, respectively, were included. Head and neck postures were determined by craniocervical, pitch, roll, and yaw angles. Pre- and post-operative pharyngeal airway volumes, pharyngeal surface area, minimum retropalatal cross-sectional areas (RP CSA) and retroglossal (RG) CSA and associated anteroposterior distances were measured using Mimics 22.0 (Materialise; Leuven, Belgium). Comparison was done using Kruskal-Wallis tests and linear mixed-effects models controlling for head and neck postures. RESULTS: Ten patients met inclusion criteria. Mean age at pre-distractor placement computed tomography scan was 99 ±â€Š35 months, and mean duration between pre- and post-surgery scans was 220 ±â€Š90 days. Head and neck posture were found to be significant predictors of all airway dimensions. After controlling for significant factors with fixed effects linear modeling, surface area was found to be significantly smaller in patients after MDO by 189.48 mm2 (F[10.8] = -3.47, P = 0.0053), compared to their preoperative measurements. Surgery was not a significant predictor of changes in airway volume (F[11.6] = 0.52, P = 0.61), minimum RP CSA (F[12.2] =  -0.64, P = 0.53), minimum RG CSA (F[12.6] =  -1.64, P = 0.13), RP anteroposterior distance (F[14.0] = 0.30, P = 0.77), or RG anteroposterior distance (F[20.0] =  -0.04, P = 0.97). CONCLUSIONS: Oblique vector MDO in patients with HFM is associated only with statistically significant changes in the surface area of the upper airway, and is not associated with statistically significant changes in dimensions like volume, CSA, or anteroposterior dimension. This is an important finding, as it may guide discussions surrounding risk/benefit ratio for MDO in childhood.

Sagittal and Vertical Growth of the Maxillo-Mandibular Complex in Untreated Children: A Longitudinal Study on Lateral Cephalograms Derived from Cone Beam Computed Tomography.

The aim of this longitudinal study was to evaluate the sagittal and vertical growth of the maxillo-mandibular complex in untreated children using orthogonal lateral cephalograms compressed from cone beam computed tomography (CBCT). Two sets of scans, on 12 males (mean 8.75 years at T1, and 11.52 years at T2) and 18 females (mean 9.09 years at T1, and 10.80 years at T2), were analyzed using Dolphin 3D imaging. The displacements of the landmarks and rotations of both jaws relative to the cranial base were measured using the cranial base, and the maxillary and mandibular core lines. From T1 to T2, relative to the cranial base, the nasion, orbitale, A-point, and B-point moved anteriorly and inferiorly. The porion moved posteriorly and inferiorly. The ANB and mandibular plane angle decreased. All but one subject had forward rotation in reference to the cranial base. The maxillary and mandibular superimpositions showed no sagittal change on the A-point and B-point. The U6 and U1 erupted at 0.94 and 1.01 mm/year (males) and 0.82 and 0.95 mm/year (females), respectively. The L6 and L1 erupted at 0.66 and 0.88 mm/year (males), and at 0.41 mm/year for both the L6 and the L1 (females), respectively.

Transverse Growth of the Maxillo-Mandibular Complex in Untreated Children: A Longitudinal Cone Beam Computed Tomography Study.

The aim of this study is to evaluate the longitudinal transverse growth of the maxillo-mandibular complex in untreated children using the Cone Beam Computed Tomography (CBCT). Two sets of scans on 12 males (mean 8.75 years at T1 and 11.52 years at T2) and 18 females (mean 9.09 years at T1 and 10.80 years at T2) were analyzed using Dolphin 3D imaging. The transverse widths of various maxillary and mandibular skeletal landmarks and the dentoalveolar and dental landmarks at the level of first molars were measured. Overall, there were greater increases in the transverse dimension in the posterior than anterior portions of the maxilla and mandible. The increase in intergonial width of the mandible seems to be primarily due to the lengthening of the mandibular body. The dentoalveolar process at the first molar level increases at an equal rate corono-apically and is independent to the changes in molar inclination. When comparing maxillary dentoalveolar changes with that of the mandible, greater increases were noticed in the maxilla, which might be explained by the presence of sutural growth in the maxilla. Moreover, the first molars maintain their coordination with each other despite the differential increase in the maxillary and mandibular dentoalveolar processes.

Mechanistic Insight into Orthodontic Tooth Movement Based on Animal Studies: A Critical Review.

Alveolar bone remodeling in orthodontic tooth movement (OTM) is a highly regulated process that coordinates bone resorption by osteoclasts and new bone formation by osteoblasts. Mechanisms involved in OTM include mechano-sensing, sterile inflammation-mediated osteoclastogenesis on the compression side and tensile force-induced osteogenesis on the tension side. Several intracellular signaling pathways and mechanosensors including the cilia and ion channels transduce mechanical force into biochemical signals that stimulate formation of osteoclasts or osteoblasts. To date, many studies were performed in vitro or using human gingival crevicular fluid samples. Thus, the use of transgenic animals is very helpful in examining a cause and effect relationship. Key cell types that participate in mediating the response to OTM include periodontal ligament fibroblasts, mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Intercellular signals that stimulate cellular processes needed for orthodontic tooth movement include receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-α (TNF-α), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), sclerostin, transforming growth factor beta (TGF-ß), and bone morphogenetic proteins (BMPs). In this review, we critically summarize the current OTM studies using transgenic animal models in order to provide mechanistic insight into the cellular events and the molecular regulation of OTM.

Osteoblast lineage cells and periodontal ligament fibroblasts regulate orthodontic tooth movement that is dependent on Nuclear Factor-kappa B (NF-kB) activation.

OBJECTIVES: To investigate the role of NF-κB in osteoblast lineage cells and periodontal ligament (PDL) fibroblasts during orthodontic tooth movement (OTM). MATERIALS AND METHODS: Transgenic mice that expressed a dominant negative mutant of the inhibitor of kB kinase (IKK-DN) with lineage specific expression in osteoblastic cells and PDL fibroblasts driven by a response element in the collagen1α1 promoter and matched wild-type (WT) mice were examined. A 10-12 g force was applied by a NiTi coil and maintained for 5 or 12 days. OTM distance, PDL width, and bone volume fraction were measured using micro computed tomography. Osteoclast numbers were counted in tartrate-resistant acid phosphatase-stained sections. Activation of nuclear factor kappa B (NF-kB) was assessed by nuclear localization of p65, and the receptor activator of nuclear factor-κB ligand (RANKL) was measured by immunofluorescence and compared to control specimens with no orthodontic force. RESULTS: OTM-induced NF-kB activation (p65 nuclear localization) in WT mice was largely blocked in transgenic (TG) mice. OTM was significantly reduced in the TG mice compared to WT mice along with reduced osteoclastogenesis, narrower PDL width, higher bone volume fraction, and reduced RANKL expression. CONCLUSIONS: Osteoblast lineage cells and PDL fibroblasts are key contributors to alveolar bone remodeling in OTM through IKKß dependent NF-κB activation.

The Biocreative Strategy. Part 6: Class III Treatment.

Distalization of mandibular molars has always been one of the most challenging treatment objectives in clinical orthodontics, particularly in adult patients.(1) If the posterior space is sufficient and alveolar bone is available, however, lower molar distalization is a viable option in Class III nonextraction therapy. Several intraoral appliances have been introduced for this purpose, including the lip bumper,(2,3) a distal extension lingual arch,(4) the Jones Jig,(*5) the Franzulum appliance,(6) and the multiloop edgewise archwire (MEAW),(7) Today, molars can be moved distally using miniscrew anchorage, with no need for patient cooperation, to camouflage a Class III malocclusion or relieve crowding without premolar extractions.

FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds.

Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage-specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to reduced endothelial cell proliferation, reduced angiogenesis, and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound-healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement.

The bone remodeling process in response to orthodontic forces requires the activity of osteoclasts to allow teeth to move in the direction of the force applied. Receptor activator of nuclear factor-κB ligand (RANKL) is essential for this process although its cellular source in response to orthodontic forces has not been determined. Orthodontic tooth movement is considered to be an aseptic inflammatory process that is stimulated by leukocytes including T and B lymphocytes which are presumed to stimulate bone resorption. We determined whether periodontal ligament and bone lining cells were an essential source of RANKL by tamoxifen induced deletion of RANKL in which Cre recombinase was driven by a 3.2 kb reporter element of the Col1α1 gene in experimental mice (Col1α1.CreERTM+.RANKLf/f) and compared results with littermate controls (Col1α1.CreERTM-.RANKLf/f). By examination of Col1α1.CreERTM+.ROSA26 reporter mice we showed tissue specificity of tamoxifen induced Cre recombinase predominantly in the periodontal ligament and bone lining cells. Surprisingly we found that most of the orthodontic tooth movement and formation of osteoclasts was blocked in the experimental mice, which also had a reduced periodontal ligament space. Thus, we demonstrate for the first time that RANKL produced by periodontal ligament and bone lining cells provide the major driving force for tooth movement and osteoclastogenesis in response to orthodontic forces.

FOXO1 deletion in keratinocytes improves diabetic wound healing through MMP9 regulation.

Keratinocyte migration is a key aspect of re-epithelialization during wound healing. Matrix metalloproteinase 9 (MMP9) contributes to this process and deficiencies in the MMP9 lead to impaired healing. Inappropriate expression of MMP9 also contributes to impaired re-epithelialization. Previously we demonstrated that FOXO1 was activated in wound healing but to higher levels in diabetic wounds. To address mechanisms of impaired re-epithelialization we examined MMP9 expression in vivo in full thickness dermal scalp wounds created in experimental K14.Cre + .Foxo1 L/L mice with lineage-specific Cre recombinase deletion of floxed FOXO1 and compared the results to control littermates. MMP9 was induced during wound healing but at a significantly higher level in diabetic compared to normal wounds. FOXO1 deletion substantially blocked this increase. By chromatin immunoprecipitation FOXO1 was shown to bind to the MMP9 promoter, FOXO1 overexpression increased MMP9 transcriptional activity and increased MMP9 expression stimulated by high glucose was blocked by FOXO1 deletion or FOXO1 knockdown. We also show for the first time that high glucose impairs keratinocyte migration by inducing high levels of MMP9 expression and establish that it involves FOXO1. Thus, FOXO1 drives high levels of MMP9 expression in diabetic wound healing, which represents a novel mechanism for impaired re-epithelization in diabetic wounds.

Wide Linear Corticotomy and Anterior Segmental Osteotomy Under Local Anesthesia Combined Corticision for Correcting Severe Anterior Protrusion With Insufficient Alveolar Housing.

BACKGROUNDS: This article presents an alternate surgical treatment method to correct a severe anterior protrusion in an adult patient with an extremely thin alveolus. To accomplish an effective and efficient anterior segmental retraction without periodontal complications, the authors performed, under local anesthesia, a wide linear corticotomy and corticision in the maxilla and an anterior segmental osteotomy in mandible. METHODS: In the maxilla, a wide linear corticotomy was performed under local anesthesia. In the maxillary first premolar area, a wide section of cortical bone was removed. Retraction forces were applied buccolingually with the aid of temporary skeletal anchorage devices. Corticision was later performed to close residual extraction space. In the mandible, an anterior segmental osteotomy was performed and the first premolars were extracted under local anesthesia. RESULTS: In the maxilla, a wide linear corticotomy facilitated a bony block movement with temporary skeletal anchorage devices, without complications. The remaining extraction space after the bony block movement was closed effectively, accelerated by corticision. In the mandible, anterior segmental retraction was facilitated by an anterior segmental osteotomy performed under local anesthesia. Corticision was later employed to accelerate individual tooth movements. CONCLUSIONS: A wide linear corticotomy and an anterior segmental osteotomy combined with corticision can be an effective and efficient alternative to conventional orthodontic treatment in the bialveolar protrusion patient with an extremely thin alveolar housing.

FOXO1 mediates RANKL-induced osteoclast formation and activity.

We have previously shown that the transcription factor FOXO1 is elevated in conditions with high levels of bone resorption. To investigate the role of FOXO1 in the formation of osteoclasts, we examined mice with lineage-specific deletion of FOXO1 in osteoclast precursors and by knockdown of FOXO1 with small interfering RNA. The receptor activator for NF-κB ligand (RANKL), a principal bone-resorbing factor, induced FOXO1 expression and nuclear localization 2 d after stimulation in bone marrow macrophages and RAW264.7 osteoclast precursors. RANKL-induced osteoclast formation and osteoclast activity was reduced in half in vivo and in vitro with lineage-specific FOXO1 deletion (LyzM.Cre(+)FOXO1(L/L)) compared with matched controls (LyzM.Cre(-)FOXO1(L/L)). Similar results were obtained by knockdown of FOXO1 in RAW264.7 cells. Moreover, FOXO1-mediated osteoclast formation was linked to regulation of NFATc1 nuclear localization and expression as well as a number of downstream factors, including dendritic cell-specific transmembrane protein, ATP6vod2, cathepsin K, and integrin αv. Lastly, FOXO1 deletion reduced M-CSF-induced RANK expression and migration of osteoclast precursors. In the present study, we provide evidence that FOXO1 plays a direct role in osteoclast formation by mediating the effect of RANKL on NFATc1 and several downstream effectors. This is likely to be significant because FOXO1 and RANKL are elevated in osteolytic conditions.