Thread shape, cortical bone thickness, and magnitude and distribution of stress caused by the loading of orthodontic miniscrews: finite element analysis.

Cortical bone thickness is assumed to be a major factor regulating miniscrew stability. We investigated stress distribution in two miniscrews with different thread shapes (type A and B) and in cortical bone of three different thicknesses using three-dimensional (3D) finite element (FE) models. More specifically, 3D FE models of two different miniscrews were created and placed obliquely or vertically into a cylindrical bone model representing different cortical bone thicknesses. When force was applied to the miniscrew, the stress distribution on the screw surface and in the peri-implant bone was assessed using FE methodology. Miniscrew safety was evaluated using a modified Soderberg safety factor. Screw head displacement increased with a decrease in cortical bone thickness, irrespective of screw type. The smallest minimum principal stresses on the screw surfaces remained constant in type A miniscrews on changes in cortical bone thickness. Minimum principal stresses also appeared on the cortical bone surface. Lower absolute values of minimum principal stresses were seen in type A miniscrews when placed vertically and with upward traction in obliquely placed type B miniscrews. Both miniscrews had acceptable safety factor values. Taken together, orthodontists should select and use the suitable miniscrew for each patient in consideration of bone properties.

Signs, Symptoms, and Morphological Features of Idiopathic Condylar Resorption in Orthodontic Patients: A Survey-Based Study.

BACKGROUND: Idiopathic condylar resorption (ICR) is an aggressive degenerative disease of the temporomandibular joint that is most frequently observed in teenage girls. However, no specific cause of ICR has been identified. To explore the specific causes of the onset and progression of ICR, we performed a survey-based study on ICR in orthodontic patients and described its subjective symptoms, clinical signs, and condylar morphological features. METHODS: A total of 1735 participants were recruited from 2193 orthodontic patients. For each participant, subjective symptoms and clinical signs of temporomandibular disorders (TMDs) were evaluated through clinical examination and a questionnaire. Furthermore, three-dimensional computed tomography (CT) was performed to diagnose ICR. RESULTS: Among the 1735 patients evaluated, ICR was present in two male and ten female patients. All 12 patients had maxillary protrusion and an anterior open bite. Four patients with ICR underwent orthodontic treatment. Based on CT findings, patients with ICR had significantly different condylar sizes and shapes from patients with TMDs alone. CONCLUSIONS: The coexistence of intrinsic and extrinsic factors, such as sex-hormone imbalance and a history of orthodontic treatment, might lead to the onset of ICR. We suggest that growing patients suspected of having ICR should undergo CT evaluation because CT findings may precede clinical symptoms and signs.

HIF-1α controls palatal wound healing by regulating macrophage motility via S1P/S1P1 signaling axis.

OBJECTIVES: To investigate the role of hypoxia-inducible factor 1α (HIF-1α) signaling, the expression profile of M1 and M2 macrophages, and the role of the sphingosine 1-phosphate (S1P)/S1P receptor system in palatal wound healing of heterozygous HIF-1α-deficient (HIF-1α HET) mice. MATERIALS AND METHODS: HIF-1α HET and wild-type (WT) littermates underwent palatal tissue excision at the mid-hard palate. Histological analysis, immunostaining, real-time PCR, Western blotting (WB), and cellular migration assays were performed to analyze wound closure and macrophage infiltration. RESULTS: DMOG pretreatment showed an acceleration of palatal wound closure in WT mice. In contrast, the delayed palatal wound closure was observed in HIF-1α HET mice with diminished production of Col1a1, MCP-1, and MIP-1α, compared with WT mice. Decreased infiltration of M1 macrophage (F4/80+ TNF-α+ , F4/80+ iNOS+ ) and M2 macrophage (F4/80+ Arginase-1+ , F4/80+ CD163+ ) was observed. The numbers of F4/80+ S1P1 + macrophages of HIF-1α HET wounded tissues were significantly lower compared with WT tissues. S1P treatment of bone marrow macrophages (BMMs) significantly upregulated expression of S1P1 in WT mice compared with HIF-1α HET. Phosphorylation of MAPK rapidly decreased in BMMs of HIF-1α HET mice than in BMMs of WT mice by S1P stimulation. Moreover, S1P enhanced HIF-1α expression via S1P1 receptors to affect macrophage migration. CONCLUSIONS: HIF-1α deficiency aggravates M1 and M2 macrophage infiltration and controls macrophage motility via S1P/S1P1 signaling. These results suggest that HIF-1α signaling may contribute to the regulation of palatal wound healing.

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling.

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.

The immunoregulatory role of p21 in the development of the temporomandibular joint-osteoarthritis.

OBJECTIVE: We aimed to identify the immunoregulatory role of the cyclin-dependent kinase inhibitor p21 in the homeostasis of mandibular condylar cartilage affected by mechanical stress. MATERIALS AND METHODS: Ten C57BL/6 wild-type (WT) and ten p21-/- mice aged 8 weeks were divided into the untreated and treated groups. In the treated groups, mechanical stress was applied to the temporomandibular joint (TMJ) through forced mouth opening for 3 hr/day for 7 days. The dissected TMJs were assessed using micro-CT, histology, and immunohistochemistry. RESULTS: Treated p21-/- condyles with mechanical stress revealed more severe subchondral bone destruction, with thinner cartilage layers and smaller proteoglycan area relative to treated WT condyles; untreated WT and p21-/- condyles had smoother surfaces. Immunohistochemistry revealed significant increases in the numbers of caspase-3, interleukin-1ß, matrix metalloprotease (MMP)-9, and MMP-13 positive cells, and few aggrecan positive cells, in treated p21-/- than in treated WT samples. Moreover, the number of TUNEL positive cells markedly increased in p21-/- condyles affected by mechanical stress. CONCLUSIONS: Our findings indicate that p21 in chondrocytes contributes to regulate matrix synthesis via the control ofm aggrecan and MMP-13 expression under mechanical stress. Thus, p21 might regulate the pathogenesis of osteoarthritis in the TMJ.

Long-term Management of a Patient with Apert Syndrome.

AIM AND OBJECTIVE: To present an Apert syndrome patient with midfacial growth deficiency treated with Le Fort III distraction osteogenesis and subsequent two-jaw surgery. BACKGROUND: Apert syndrome is expressed as a severe and irregular craniosynostosis, midfacial hypoplasia, and symmetric syndactyly in the fingers and toes. For craniosynostosis syndromes, treatment planning is complex due to the disharmony between facial profile and occlusion. CASE DESCRIPTION: A 4-year-and-5-month-old boy, diagnosed with Apert syndrome, showed a concave profile accompanied with midfacial hypoplasia, moderate exorbitism, a reversed occlusion of -10.0 mm, an anterior open bite of -5.0 mm, and skeletal class III jaw-base relationship. The patient, aged 15 years and 4 months, underwent a Le Fort III osteotomy, and subsequent osteodistraction was performed via a rigid external distraction (RED) device. His midfacial bone was advanced by approximately 7.0 mm. One year after the distraction, preoperative treatment with 0.018-in preadjusted edgewise appliances was initiated. Two-jaw surgery with a Le Fort I osteotomy and bilateral sagittal split ramus osteotomy was performed after 42 months of preoperative orthodontic treatment. At the age of 20 years and 9 months, his facial profile dramatically changed to a straight profile, and an acceptable occlusion with an adequate interincisal relationship was obtained. A functional occlusion with an excellent facial profile was maintained throughout the 2-year retention period, although the upper dental arch width was slightly decreased, resulting in the recurrence of the left posterior crossbite. CONCLUSION: Our report indicates the necessity of long-term follow-up in patients with craniosynostosis because of syndrome-specific growth and methodologically induced relapse. CLINICAL SIGNIFICANCE: The two-stage operation combining early distraction osteogenesis and postgrowth orthognathic surgery proves to be an effective therapy for correcting midfacial hypoplasia and skeletal mandibular protrusion caused by Apert syndrome.

Protective Effects of Low-Intensity Pulsed Ultrasound on Mandibular Condylar Cartilage Exposed to Mechanical Overloading.

The aim of this study was to assess the effect of low-intensity pulsed ultrasound (LIPUS) application on rat temporomandibular joints (TMJs) with early-stage of osteoarthritis-like conditions induced by mechanical overloading. Fifteen-week-old male Wistar rats were divided into two experimental groups and a control group (n = 10 each). Both TMJs of all rats in one experimental group were subjected to mechanical overloading for 5 d, and those in the other experimental group were exposed to LIPUS for 20 min/d after overloading. Condyles were assessed using micro-computed tomography, histology and histomorphometry. LIPUS treatment attenuated cartilage degeneration, decreased the number of osteoclastic cells and restored the expression of aggrecan after an initial decrease induced by mechanical overloading. These results indicate that LIPUS may have a protective effect on the early progression of TMJ osteoarthritis.

Skeletal anchorage for intrusion of bimaxillary molars in a patient with skeletal open bite and temporomandibular disorders.

The treatment of severe skeletal anterior open bite is extremely difficult in adults, and orthognathic surgery is generally selected for its treatment. We report the case of an 18-year-old adult patient with skeletal anterior open bite and temporomandibular disorders who was successfully treated using temporary anchorage devices. She had an open bite of -2.0 mm and an increased facial height. Miniplates were implanted in both the maxilla and mandible, and molar intrusion resulted in counterclockwise rotation of the mandible over a period of 12 months. After active treatment, her upper and lower first molars were intruded by approximately 2 mm and her overbite became +2.5 mm. Her retrognathic profile improved with counterclockwise rotation of the mandible. Orthodontic treatment aided with skeletal anchorage is beneficial for intrusion of bimaxillary molars in patients with anterior open bite.

Fas/S1P1 crosstalk via NF-κB activation in osteoclasts controls subchondral bone remodeling in murine TMJ arthritis.

Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/lpr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/lpr mice due to enhanced phosphorylation of NF-κB, as well as Akt and MAPK, to receptor activator of nuclear factor-κB ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (S1P1) was also significantly upregulated in the condylar cartilage. S1P1 was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-κB-inhibitory peptide, was applied to the MRL/lpr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P1 signaling were reduced. Thus, the present results suggest that Fas/S1P1 signaling via activation of NF-κB in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ.

Correction: Rebamipide Attenuates Mandibular Condylar Degeneration in a Murine Model of TMJ-OA by Mediating a Chondroprotective Effect and by Downregulating RANKL-Mediated Osteoclastogenesis.

[This corrects the article DOI: 10.1371/journal.pone.0154107.].

Rebamipide Attenuates Mandibular Condylar Degeneration in a Murine Model of TMJ-OA by Mediating a Chondroprotective Effect and by Downregulating RANKL-Mediated Osteoclastogenesis.

Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by progressive degradation of cartilage and changes in subchondral bone. It is also one of the most serious subgroups of temporomandibular disorders. Rebamipide is a gastroprotective agent that is currently used for the treatment of gastritis and gastric ulcers. It scavenges reactive oxygen radicals and has exhibited anti-inflammatory potential. The aim of this study was to investigate the impact of rebamipide both in vivo and in vitro on the development of cartilage degeneration and osteoclast activity in an experimental murine model of TMJ-OA, and to explore its mode of action. Oral administration of rebamipide (0.6 mg/kg and 6 mg/kg) was initiated 24 h after TMJ-OA was induced, and was maintained daily for four weeks. Rebamipide treatment was found to attenuate cartilage degeneration, to reduce the number of apoptotic cells, and to decrease the expression levels of matrix metalloproteinase-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in TMJ-OA cartilage in a dose-dependent manner. Rebamipide also suppressed the activation of transcription factors (e.g., NF-κB, NFATc1) and mitogen-activated protein kinases (MAPK) by receptor activator of nuclear factor kappa-B ligand (RANKL) to inhibit the differentiation of osteoclastic precursors, and disrupted the formation of actin rings in mature osteoclasts. Together, these results demonstrate the inhibitory effects of rebamipide on cartilage degradation in experimentally induced TMJ-OA. Furthermore, suppression of oxidative damage, restoration of extracellular matrix homeostasis of articular chondrocytes, and reduced subchondral bone loss as a result of blocked osteoclast activation suggest that rebamipide is a potential therapeutic strategy for TMJ-OA.

Aromatase controls Sjögren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages.

Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArKO mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjögren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjögren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage.

Anti-inflammatory effects of rebamipide eyedrop administration on ocular lesions in a murine model of primary Sjögren's syndrome.

BACKGROUND: Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown. METHODS AND FINDING: Reb eyedrops were administered to the murine model of SS aged 4-8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment. CONCLUSION: Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.