A three-dimensional investigation of mandibular deviation in patients with mandibular prognathism.

BACKGROUND: Craniofacial disharmony in cases of jaw deformity associated with abnormal lateral deviation of the jaw mostly involves both the maxilla and mandible. However, it has been still difficult to capture the jaw deviation aspect in a 3-dimensional and quantitative techniques. In this study, we focused on 3-dimensional mandibular morphology and position of the condylar head in relation to the base of the skull in patients with mandibular prognathism, one of the most common jaw deformities. We used cluster analysis to quantify and classify deviation and clarified its characteristics. We also investigated the degree of correlation between those findings and menton (Me) deviation measured on frontal cephalograms, which is a conventional indicator of jaw deformity. RESULTS: Findings obtained from 100 patients (35 men, 65 women) were classified into the following three groups based on mandibular morphology and condylar position relative to the skull base. Then, reclassification using these parameters enabled classification of cluster analysis findings into seven groups based on abnormal jaw deviation characteristics. Comparison among these seven groups showed that the classification criteria were ramus height, mandibular body length, distance from the gonion to the apex of the coronoid process, and the lateral and vertical positions of the mandible. Weak correlation was also found between Me deviation on frontal cephalograms and each of the above parameters measured on 3D images. CONCLUSIONS: Focusing on mandibular morphology and condylar position relative to the skull base in patients with mandibular prognathism, we used cluster analysis to quantify and classify jaw deviation. The present results showed that the 3D characteristics of the mandible based on mandibular morphology and condylar position relative to the skull base can be classified into seven groups. Further, we clarified that Me deviation on frontal cephalograms, which has been used to date, is inadequate for capturing jaw deviation characteristics.

Occlusal Evaluation Using Modified Huddart and Bodenham Scoring System Following 2-Stage Palatoplasty With Hotz Plate: A Comparison Among 3 Different Surgical Protocols.

OBJECTIVE: This study aimed to determine if the change in technique of soft palate closure or timing of hard palatal repair induced occlusal changes in patients with complete unilateral cleft lip and palate (CUCLP). DESIGN: Retrospective study. SETTINGS: A medical and dental hospital in Japan. SUBJECTS: A total of 96 patients with CUCLP treated with 2-stage palatoplasty were included in the study and categorized into 3 groups (G1, G2, and G3) according to the protocol used. INTERVENTIONS: G1 underwent soft palate repair using Perko method at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. Furlow method was used for soft palate repair in G2 at 1.5 years of age and hard palate repair using vomer flap procedure at 5.5 years of age. The Furlow method was used to repair the soft palate in G3 at 1.5 years of age and vomer flap procedure was used to repair the hard palate at 4 years of age. MAIN OUTCOME MEASURES: Two evaluators assessed the dental arch relationship using the modified Huddart/Bodenham (mHB) index on 2 separate occasions. RESULTS: Intra- (intraclass correlation coefficient [ICC]: 0.962) and inter-examiner (ICC: 0.950) reliability showed very good agreement. The frequency of crossbite present in the major and minor segments gradually decreased with each change in protocol. Mean segmental scores showed no significant difference between 3 protocols (P > .05). Good inter-arch alignment occurred with all 3 surgical protocols (G1:82.6%, G2:89.8%, and G3:91.7%). CONCLUSIONS: There was no significant difference in the dental arch relationship outcomes between the 3 surgical protocols. The dentition status was comparable with all surgical protocols, even after the changes.

Dental Arch Relationship Outcomes Following 2-Stage Palatoplasty for Japanese Patients With Complete Unilateral Cleft Lip and Palate: A 3-Center Study.

OBJECTIVE: To compare dental arch relationship outcomes following 3 different 2-stage palatal repair protocols. DESIGN: Retrospective, cross sectional. SETTING: Three cleft palate centers (A, B, C) in Japan. PATIENTS: Ninety (A: 39, B: 26, C: 25) consecutively treated Japanese patients with complete unilateral cleft lip and palate. INTERVENTIONS: In A, the soft palate and the posterior half of the hard palate were repaired at a mean age of 1 year 7 months. In B, the soft palate and hard palate were closed separately at a mean age of 1 year 6 months and 5 years 8 months, respectively. In C, the soft palate and hard palate were closed at a mean age of 1 year and 1 year 5 months, respectively. MAIN OUTCOME MEASURES: Dental arch relationships were assessed using the 5-Year-Olds' (5-Y) index by 5 raters and the Huddart/Bodenham (HB) index by 2 raters. RESULTS: Intra- and inter-rater reliabilities showed substantial or almost perfect agreement for the 5-Y and HB ratings. No significant differences in mean values and distributions of 5-Y scores were found among the 3 centers. The mean HB index scores of molars on the minor segment were significantly smaller in C than those in A and B (P < .05). CONCLUSIONS: There were no significant differences in dental arch relationships at 5 years among the times and techniques of hard palate closure. However, further analysis of the possible influence of infant cleft size as a covariable on a larger sample size is needed.

Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients.

OBJECTIVES: This retrospective study examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for oral mucositis (OM) affected head-and-neck cancer (HNC) patients receiving concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint. The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. RESULTS: The group managed by PEMT had significantly lower weight loss and a significantly lower incidence of local anesthetic and opioid use and switch to tape compared with the group not managed by PEMT (p<0.05). The two groups showed no significant difference in OM (yes/no) or OM severity. The PEMT group had significantly shorter LOD at 57 (53-64) days compared with the non-PEMT group at 63.5 (57-68) days (p<0.05). CONCLUSIONS: Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, the PEMT group had a lower incidence of grades 3 and 4 OM than the non-PEMT group, although not significantly. In addition, PEMT contributed to oral pain relief and the lowering of the risk for OM by reduction in weight loss.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders in the oral cavity: a clinicopathologic study of 4 cases and literature review.

OBJECTIVES: Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OI-LPD) have been reported as one of the adverse effects of immunosuppressive therapy. The aim of this study was to describe the clinicopathologic and immunohistochemical features of OI-LPD in the oral cavity. STUDY DESIGN: Immunohistochemistry was performed to describe the immunohistochemical features in our 4 cases. The results were analyzed along with 62 cases of oral OI-LPD in the English and Japanese literature to define clinical and pathologic characteristic features. RESULTS: In our immunohistochemical analysis, Epstein-Barr virus (EBV)-positive OI-LPD showed a higher percentage of mouse double minute 2-positive cells than EBV-negative samples. A literature survey revealed that OI-LPD (including the present cases) arises primarily in the gingiva, followed by the tongue, and usually occurs with a male-to-female ratio of 1:1.9. The rate of EBV positivity was 93.8%. Further, 31 of 66 patients had osteonecrosis of the jaw and 24 of 31 patients had taken multiple immunosuppressive drugs in combination. CONCLUSIONS: We can therefore conclude that the overexpression of mouse double minute 2 in OI-LPD is associated with EBV infection, and the combination of multiple immunosuppressive drugs may be a risk factor for osteonecrosis of the jaw.

Identification and characterization of R2TP in the development of oral squamous cell carcinoma.

R2TP is a well-conserved molecular chaperone complex, composed of Pontin, Reptin, RPAP3, and PIH1D, in eukaryotes. Recent studies have suggested an involvement of R2TP in cancer development. However, it remains unclear if it is related to the development of oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer. Here, we identify and investigate the function of R2TP in OSCC development. Immunohistochemical analysis reveals that all of the R2TP components are strongly expressed in normal oral epithelia and OSCC tissues, where actively proliferating cells are abundant. Co-immunoprecipitation assay identifies that R2TP components form a protein complex in OSCC-derived HSC4-cells. Knockdown experiments show that all R2TP components, except for RPAP3, are required for the cell proliferation and migration of HSC-4 cells. Furthermore, we reveal that Pontin contributes to a gain-of-function (GOF) activity of mutp53-R248Q in HSC-4 cells by regulating phosphorylation levels of mutp53 at Ser15 and Ser46. To our knowledge, this study is the first to report the functional involvement of R2TP and its components in the malignant characteristics of OSCC cells.

Comparison between the prophylactic effects of amoxicillin 24 and 48 hours pre-operatively on surgical site infections in Japanese patients with impacted mandibular third molars: A prospective cohort study.

INTRODUCTION: According to the guidelines, the dosage for mandibular wisdom tooth extraction (MWTE) varies within the administration period. There is a 24-fold difference between the minimum and maximum doses. If an appropriate antimicrobial can be administered without increasing incidence of surgical site infection (SSI), it may lead to a global action plan on antimicrobial resistance (AMR). Therefore, we prospectively surveyed incidence of SSI post-operatively and use of oral antibiotics (OA) for MWTE. METHODS: Subjects were patients who underwent MWTE in our dental outpatient clinic from May 2019 to April 2020. Two groups were formed depending on type of administration period they received: 24 h and 48 h after surgery. The following information was collected: (1) patient factors (age, gender, body mass index, presence/absence of preoperative medication, diagnosis, impacted wisdom tooth status; (2) surgical factors (operative time, presence/absence of closure, presence/absence of hemostat, doctor career, type and frequency of painkiller); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. RESULTS: Three hundred forty subjects were analyzed, all of which used amoxicillin. There were 106 cases in 24 h group and 234 cases in 48 h group. The total incidence of SSI was 1.1% (4/340 cases), with 0.9% (1/106 cases) in 24 h group and 1.3% (3/234 cases) in 48 h group; there was no difference between the two groups. CONCLUSION: Our study suggests that amoxicillin (250 mg/dose every 8 h x 3 doses beginning 1 h before surgery) might be sufficient in preventing SSI in Japanese dental patients without SSI risk factors.

Saliva as a potential matrix for evaluating pharmacologically active dolutegravir concentration in plasma.

Therapeutic drug monitoring (TDM) is used in certain clinically selected cases and in research settings to optimize the response to antiretroviral therapy. Plasma of blood is commonly used for TDM, but blood sampling is invasive and at risk for transmission of infectious agents. On the other hand, saliva sampling is noninvasive, safe, cheap, and easily performed compared to blood. Dolutegravir (DTG) is now widely prescribed as a key component of antiretroviral therapy for HIV infection. In this study, we examined the relationship between DTG concentrations in plasma and saliva of treated patients to explore the possibility of using saliva as an alternative body fluid of TDM. A total of 17 pairs of blood and saliva samples were obtained from 15 consented HIV-1-infected subjects treated with DTG containing regimens for more than one month. Both blood and saliva samples were collected within 1 h of each other. Drug concentrations were determined by liquid chromatography-tandem mass spectrometry using DTG-d5 as an internal standard. The LLOQ was 0.5 ng/mL. The calibration curves were prepared with pooled plasma or saliva containing DTG in a range of 0.5-100 ng/mL with precision of <14.4% and accuracy within ±14.7%. The DTG concentrations in the plasma and saliva were significantly correlated (Pearson's correlation coefficient r = 0.76, p < 0.001). The median ratio of the drug concentration in saliva to those in plasma was 0.0056, which is close to the rate of non-protein-bound DTG in plasma (0.70%), suggesting that only free DTG in plasma is transported to the salivary glands and secreted into saliva. The present study demonstrates that DTG concentration in saliva reflects the pharmacologically active drug concentration in plasma and may provide an easily accessible alternative for monitoring effective antiretroviral treatment.

Risk Factors for Post-Tooth Extraction Complications in HIV-Infected Patients: a Retrospective Study.

We aimed to assess the rate and risk factors of postoperative complications following tooth extraction in HIV-infected patients by CD4 count. The study participants were 231 HIV-infected patients who underwent tooth extraction at our institution between January 2007 and December 2011. Blood test results, underlying diseases, surgical site, extraction method, and postoperative complication data were obtained from medical records. Potential risk factors of postoperative complications were analyzed using multivariate logistic regression. Patients were divided into two groups: 61 (26%) patients with a CD4 count < 200/µL, and 170 (74%) with a CD4 count ≥ 200/µL. Of the 231 patients, 12 (5.2%) developed postoperative complications (alveolar osteitis, n = 10; surgical site infection, n = 2). The rate of complications did not differ between the CD4 < 200/µL group (1.6%) and the CD4 ≥200/µL group (6.5%) (adjusted odds ratio [aOR]: 9.328, 95% confidence interval [CI]: 0.470, 185.229; P = 0.1431). Surgical extraction with bone excavation, but without CD4 count, was identified as a risk factor for post-extraction complications (aOR: 22.037, 95% CI: 1.519, 319.617; P = 0.0234). A low CD4 count is not a risk factor for post-extraction complications in patients with HIV infection. We conclude that tooth extraction should be performed based on dental/oral conditions, and not delayed until CD4 count improvement.

Clinico-statistical survey of oral antimicrobial prophylaxis and surgical site infection regarding ordinary tooth extraction and mandibular wisdom tooth extraction in the dental outpatient clinic.

INTRODUCTION: We investigated the use of oral antibiotics (OA) and surgical site infection (SSI) related to extractions of ordinary teeth and mandibular wisdom teeth in a dental outpatient clinic from January 2015 to December 2019. METHODS: The following information were surveyed: (1) presence/absence of OA, (2) timing, (3) type, (4) administration period, and (5) SSI rates. RESULTS: The use of OA during ordinary tooth extraction decreased from 68.3% to 41.3%, but SSI rate did not change during this period of time. Total SSI rate was 0.8% (122/14,832) on average. For mandibular wisdom tooth extraction, preoperative administration of third-generation cephalosporins decreased from 70.4% to 0.3% while that of penicillin (AMPC) increased from 0% to 98%. SSI rate was not changed after these improvements. Total SSI rate was 3.5% (180/5106) on average. The duration of OA was slightly decreased to two days in 2018 and 2019, and it was found that there was no significant difference in SSI rates between 2- and 3-day durations. Preoperative administration had 0.37 odds ratio (OR) (95% confidence interval (95%CI): 0.22-0.63) of SSI compared with postoperative administration. AMPC had 0.76 OR (95% CI: 0.55-1.04) of SSI compared with Third-generation cephalosporins and others. Timing of OA was P < 0.01. CONCLUSIONS: SSI rates did not change over time, administration period of OA decreased and the use of AMPC increased. Therefore, it seems necessary to continue to investigate the effects of SSI risk factors proactively in the future and to make efforts in the advocacy of appropriate antimicrobial use.

Relationship between detection of hepatitis B virus in saliva and periodontal disease in hepatitis B virus carriers in Japan.

INTRODUCTION: Although hepatitis B virus infection is well-described, the additional risk posed by oral bleeding in individuals with chronic hepatitis B virus infection has not been determined. This study aimed to determine the quantity of hepatitis B virus in the saliva of carriers in Japan, as a means of understanding the potential risk for horizontal transmission. METHODS: Saliva samples from 48 confirmed hepatitis B virus carriers were included in the analysis. Hepatitis B virus concentrations and the presence of occult blood as periodontal disease were evaluated in each sample. RESULTS: Hepatitis B surface antigen was identified in 46 of the 48 samples (98%), with hepatitis B virus DNA identified in 19 of the 48 saliva samples (40%). Occult blood was detected in 32 (67%) samples with the prevalence increasing as a function of age (r = 0.413; P = 0.003). There was a significantly positive correlation between hepatitis B virus DNA levels in the serum and saliva specimens (r = 0.895; P < 0.001). CONCLUSIONS: Occult blood in saliva was detected in most participants. The detection of hepatitis B virus DNA correlated positively with hepatitis B virus in the serum and occult blood in the saliva. Therefore, improved care of periodontal disease among older people is important for preventing horizontal transmission of hepatitis B virus.

Clinical guidelines for total temporomandibular joint replacement.

Total joint replacement (TJR) of the temporomandibular joint (TMJ) is a promising surgical procedure and device for treating end-stage diseases of the TMJ. For the functional and aesthetic reconstruction of the oral and maxillofacial head and neck region, TMJ TJR significantly helps maintain the patient's quality of life in terms of a better diet, mastication, speech and social interaction. TMJ TJR was approved by regulatory authorities in 2019 in Japan, thus enabling the clinical application of the TJR system. However, the surgery demands particularly difficult and high-risk procedures, necessitating the prudent selection of indicated patients. The joint committee of the Japanese Society of Oral and Maxillofacial Surgeons and Japanese Society for Temporomandibular Joint is working together to develop an appropriate clinical guideline for TMJ TJR.

Distinct differences in hypoxic responses between human oral mucosa and skin fibroblasts in a 3D collagen matrix.

The differences between oral mucosa and skin wound healing involving hypoxic responses of fibroblasts are poorly elucidated. In this study, we aimed to study the different hypoxic responses between oral and skin fibroblasts embedded in a three-dimensional (3D) collagen matrix to address the early stage of wound healing. Primary oral mucosa fibroblasts (OMFs) obtained from the retromolar area and skin fibroblasts (SFs) obtained from the abdomen were cultured in the 3D 'floating model' under either 21%, 5% or 1% O2 for 2 days. Cell viability under hypoxia was higher in the OMFs than in the SFs. Collagen gel contraction was suppressed under hypoxic conditions in both fibroblasts, consistent with the reduction of alpha smooth muscle actin expression, except for SFs under 1% O2. Subsequently, their gene expression profiles between 21 and 1% O2 concentrations were compared via microarray technology, and the expression profiles of the extracellular matrix (ECM)-associated proteins, including matrix metalloproteinases and collagens, were evaluated. The OMFs were more susceptible to 1% O2, and more of their genes were downregulated than the SFs'. Although the production and expression levels of ECM-associated proteins in both fibroblasts diminished under hypoxia, those levels in OMFs were significantly higher than those in SFs. In the case of single origin OMFs and SFs, our findings suggest that OMFs possess a higher baseline production capacity of several ECM-associated proteins than SFs, except type III collagen. The intrinsic hypoxic responses of OMFs may be attributed to a more favourable wound healing in oral mucosa.

Antimicrobial susceptibility surveillance of bacterial isolates recovered in Japan from odontogenic infections in 2013.

We report on the findings of the first antimicrobial susceptibility surveillance study in Japan of isolates recovered from odontogenic infections. Of the 38 facilities where patients representing the 4 groups of odontogenic infections were seen, 102 samples were collected from cases of periodontitis (group 1), 6 samples from pericoronitis (group 2), 84 samples from jaw inflammation (group 3) and 54 samples from phlegmon of the jaw bone area (group 4) for a total of 246 samples. The positivity rates of bacterial growth on culture were 85.3%, 100%, 84% and 88.9%, respectively, for groups 1, 2, 3 and 4. Streptococcus spp. isolation rates according to odontogenic infection group were 22% (group 1), 17.7% (group 3) and 20.7% (group 4). Anaerobic isolation rates were 66.9% (group 1), 71.8% (group 3) and 68.2% (group 4). Drug susceptibility tests were performed on 726 strains excluding 121 strains that were undergrown. The breakdown of the strains subjected to testing was 186 Streptococcus spp., 179 anaerobic gram-positive cocci, 246 Prevotella spp., 27 Porphyromonas spp., and 88 Fusobacterium spp. The isolates were tested against 30 antimicrobial agents. Sensitivities to penicillins and cephems were good except for Prevotella spp. The low sensitivities of Prevotella spp is due to ß-lactamase production. Prevotella strains resistant to macrolides, quinolones, and clindamycin were found. No strains resistant to carbapenems or penems were found among all strains tested. No anaerobic bacterial strain was resistant to metronidazole. Antimicrobial susceptibility testing performed on the S. anginosus group and anaerobic bacteria, which are the major pathogens associated with odontogenic infections, showed low MIC90 values to the penicillins which are the first-line antimicrobial agents for odontogenic infections; however, for Prevotella spp., penicillins combined with ß-lactamase inhibitor showed low MIC90 values.

Overactivation of the NF-κB pathway impairs molar enamel formation.

OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm-derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF-κB pathway is known to be responsible for HED, it remains unclear whether this pathway is involved in the process of enamel formation. EXPERIMENTAL SUBJECTS AND METHODS: To address this question, we examined the mice overexpressing Ikkß (an essential component required for the activation of NF-κB pathway) under the keratin 5 promoter (K5-Ikkß). RESULTS: Upregulation of the NF-κB pathway was confirmed in the ameloblasts of K5-Ikkß mice. Premature abrasion was observed in the molars of K5-Ikkß mice, which was accompanied by less mineralized enamel. However, no significant changes were observed in the enamel thickness and the pattern of enamel rods in K5-Ikkß mice. Klk4 expression was significantly upregulated in the ameloblasts of K5-Ikkß mice at the maturation stage, and the expression of its substrate, amelogenin, was remarkably reduced. This suggests that abnormal enamel observed in K5-Ikkß mice was likely due to the compromised degradation of enamel protein at the maturation stage. CONCLUSION: Therefore, we could conclude that the overactivation of the NF-κB pathway impairs the process of amelogenesis.

Modulatory effects of repeated psychophysical stress on masseter muscle nociception in the nucleus raphe magnus of rats.

Psychophysical stress can cause neural changes that increase nociception in the orofacial region, particularly the masseter muscle (MM). The nucleus raphe magnus (NRM), which is located in the brain stem, serves the crucial role of regulating nociception through descending modulatory pain control. However, it remains unclear if neural activities in the NRM are affected under psychophysical stress conditions. This study conducted experiments to assess (1) whether neural activity, indicated by Fos expression in an NRM that has experienced MM injury, is affected by the stress of repeated forced swim tests (FST); and (2) whether the selective serotonin reuptake inhibitor fluoxetine administered daily after an FST could affect the number of Fos-positive neurons in the NRM. Results revealed that the stress from repeated FSTs significantly increased the number of Fos-positive neurons in an NRM that had been affected by MM injury. Fluoxetine inhibited increases in the number of Fos-positive neurons in the NRM that occurred as a result of FSTs, but this was not observed in sham rats. These findings indicate that the stress from FSTs could increase nociceptive neural activity in an NRM that has experienced MM injury. This could be due, in part, to changes in serotonergic mechanisms.

Daily administration of Sake Lees (Sake Kasu) reduced psychophysical stress-induced hyperalgesia and Fos responses in the lumbar spinal dorsal horn evoked by noxious stimulation to the hindpaw in the rats.

We tested whether Sake Lees (SL) had inhibitory effects on hyperalgesia in the hindpaw under psychophysical stress conditions. Male rats were subjected to repeated forced swim stress treatments (FST) from Day -3 to Day -1. Intraperiotoneal administration of SL which contained low concentration of ethanol (SLX) was conducted after each FST. On Day 0, formalin-evoked licking behaviors and Fos responses in the lumbar spinal cord (DH) and several areas within the rostral ventromedial medulla (RVM) were quantified as nociceptive responses. FST-induced hyperalgesia in the hindpaw was prevented by repeated SL and SLX treatments. Fos expression was significantly increased in DH and some areas within the RVM under FST, which was prevented by repeated SL or SLX. These findings indicated that daily administration of SL had the potential to alleviate stress-induced hyperalgesia.

Ift88 is involved in mandibular development.

The mandible is a crucial organ in both clinical and biological fields due to the high frequency of congenital anomalies and the significant morphological changes during evolution. Primary cilia play a critical role in many biological processes, including the determination of left/right axis patterning, the regulation of signaling pathways, and the formation of bone and cartilage. Perturbations in the function of primary cilia are known to cause a wide spectrum of human diseases: the ciliopathies. Craniofacial dysmorphologies, including mandibular deformity, are often seen in patients with ciliopathies. Mandibular development is characterized by chondrogenesis and osteogenesis; however, the role of primary cilia in mandibular development is not fully understood. To address this question, we generated mice with mesenchymal deletions of the ciliary protein, Ift88 (Ift88fl/fl ;Wnt1Cre). Ift88fl/fl ;Wnt1Cre mice showed ectopic mandibular bone formation, whereas Ift88 mutant mandible was slightly shortened. Meckel's cartilage was modestly expanded in Ift88fl/fl ;Wnt1Cre mice. The downregulation of Hh signaling was found in most of the mesenchyme of Ift88 mutant mandible. However, mice with a mesenchymal deletion of an essential molecule for Hh signaling activity, Smo (Smofl/fl ;Wnt1Cre), showed only ectopic mandibular formation, whereas Smo mutant mandible was significantly shortened. Ift88 is thus involved in chondrogenesis and osteogenesis during mandibular development, partially through regulating Sonic hedgehog (Shh) signaling.

Ift88 limits bone formation in maxillary process through suppressing apoptosis.

OBJECTIVE: The development of the maxillary bone is under strict molecular control because of its complicated structure. Primary cilia play a critical role in craniofacial development, since defects in primary cilia are known to cause congenital craniofacial dysmorphologies as a wide spectrum of human diseases: the ciliopathies. The primary cilia also are known to regulate bone formation. However, the role of the primary cilia in maxillary bone development is not fully understood. DESIGN: To address this question, we generated mice with a mesenchymal conditional deletion ofIft88 using the Wnt1Cre mice (Ift88fl/fl;Wnt1Cre). The gene Ift88 encodes a protein that is required for the function and formation of primary cilia. RESULTS: It has been shown thatIft88fl/fl;Wnt1Cre mice exhibit cleft palate. Here, we additionally observed excess bone formation in the Ift88 mutant maxillary process. We also found ectopic apoptosis in the Ift88 mutant maxillary process at an early stage of development. To investigate whether the ectopic apoptosis is related to the Ift88 mouse maxillary phenotypes, we generated Ift88fl/fl;Wnt1Cre;p53-/- mutants to reduce apoptosis. The Ift88fl/fl;Wnt1Cre;p53-/- mice showed no excess bone formation, suggesting that the cells evading apoptosis by the presence of Ift88 in wild-type mice limit bone formation in maxillary development. On the other hand, the palatal cleft was retained in the Ift88fl/fl;Wnt1Cre;p53-/- mice, indicating that the excess bone formation or abnormal apoptosis was independent of the cleft palate phenotype in Ift88 mutant mice. CONCLUSIONS: Ift88 limits bone formation in the maxillary process by suppressing apoptosis.

MicroRNAs control eyelid development through regulating Wnt signaling.

BACKGROUND: The timing, location, and level of gene expression are crucial for normal organ development, because morphogenesis requires strict genetic control. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating gene expression level. Although miRNAs are known to be involved in many biological events, the role of miRNAs in organogenesis is not fully understood. Mammalian eyelids fuse and separate during development and growth. In mice, failure of this process results in the eye-open at birth (EOB) phenotype. RESULTS: It has been shown that conditional deletion of mesenchymal Dicer (an essential protein for miRNA processing; Dicer fl/fl ;Wnt1Cre) leads to the EOB phenotype with full penetrance. Here, we identified that the up-regulation of Wnt signaling resulted in the EOB phenotype in Dicer mutants. Down-regulation of Fgf signaling observed in Dicer mutants was caused by an inverse relationship between Fgf and Wnt signaling. Shh and Bmp signaling were down-regulated as the secondary effects in Dicer fl/fl ;Wnt1Cre mice. Wnt, Shh, and Fgf signaling were also found to mediate the epithelial-mesenchymal interactions in eyelid development. CONCLUSIONS: miRNAs control eyelid development through Wnt. Developmental Dynamics 248:201-210, 2019. © 2019 Wiley Periodicals, Inc.