Msx1 is essential for proper rostral tip formation of the mouse mandible.

The right and left mandibular processes derived from the first branchial arch grow toward the midline and fuse to create the rostral tip region of the mandible during mandibular development. Severe and mild cases of failure in this process results in rare median cleft of the lower lip and cleft chin, respectively. The detailed molecular mechanisms of mandibular tip formation are unknown. We hypothesize that the Msx1 gene is involved in mandibular tip development, because Msx1 has a central role in other craniofacial morphogenesis processes, such as teeth and the secondary palate development. Normal Msx1 expression was observed in the rostral end of the developing mandible; however, a reduced expression of Msx1 was observed in the soft tissue of the mandibular tip than in the lower incisor bud region. The rostral tip of the right and left mandibular processes was unfused in both control and Msx1-null (Msx1-/-) mice at embryonic day (E) 12.5; however, a complete fusion of these processes was observed at E13.5 in the control. The fused processes exhibited a conical shape in the control, whereas the same region remained bifurcated in Msx1-/-. This phenotype occurred with 100% penetrance and was not restored at subsequent stages of development. Furthermore, Meckel's cartilage in addition to the outline surface soft tissues was also unfused and bifurcated in Msx1-/- from E14.5 onward. The expression of phosho-Smad1/5, which is a mediator of bone morphogenetic protein (Bmp) signaling, was downregulated in the mandibular tip of Msx1-/- at E12.5 and E13.5, probably due to the downregulated Bmp4 expression in the neighboring lower incisor bud. Cell proliferation was significantly reduced in the midline region of the mandibular tip in Msx1-/- at the same developmental stages in which downregulation of pSmad was observed. Our results indicate that Msx1 is indispensable for proper mandibular tip development.

Role of reactive oxygen species (ROS) in the regulation of adipogenic differentiation of human maxillary/mandibular bone marrow-derived mesenchymal stem cells.

BACKGROUND: Maxillary/mandibular bone marrow-derived mesenchymal stem cells (MBMSCs) exhibit a unique property of lower adipogenic potential than other bone marrow-derived MSCs. However, the molecular mechanisms regulating the adipogenesis of MBMSCs remain unclear. This study aimed to explore the roles of mitochondrial function and reactive oxygen species (ROS) in regulating the adipogenesis of MBMSCs. METHODS AND RESULTS: MBMSCs exhibited significantly lower lipid droplet formation than iliac BMSCs (IBMSCs). Moreover, the expression levels of CCAAT/enhancer-binding protein ß (C/EBPß), C/EBPδ, and early B cell factor 1 (Ebf-1), which are early adipogenic transcription factors, and those of peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα, which are late adipogenic transcription factors, were downregulated in MBMSCs compared to those in IBMSCs. Adipogenic induction increased the mitochondrial membrane potential and mitochondrial biogenesis in MBMSCs and IBMSCs, with no significant difference between the two cell types; however, intracellular ROS production was significantly enhanced only in IBMSCs. Furthermore, NAD(P)H oxidase 4 (NOX4) expression was significantly lower in MBMSCs than in IBMSCs. Increased ROS production in MBMSCs by NOX4 overexpression or treatment with menadione promoted the expression of early adipogenic transcription factors but did not induce that of late adipogenic transcription factors or lipid droplet accumulation. CONCLUSIONS: These results suggest that ROS may be partially involved in the process of MBMSC adipogenic differentiation from undifferentiated cells to immature adipocytes. This study provides important insights into the tissue-specific properties of MBMSCs.

Day Care Surgery for Unilateral Alveolar Bone Grafting of Residual Clefts With Mandibular Symphyseal Bone-A Prospective Questionnaire Study.

OBJECTIVE: To evaluate patients' experiences of shortened hospitalization in relation to bone grafting of unilateral alveolar clefts with mandibular symphyseal bone grafts. DESIGN: Prospective cohort questionnaire study. SETTING: Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Denmark. PATIENTS: Thirty-nine (male n = 26, female n = 13) patients with unilateral residual clefts after primary reconstruction, mean age 10.4 years. INTERVENTIONS: All patients underwent a standardized procedure with closure of the alveolar defect using mandibular symphyseal bone grafts. Patients were discharged within a day after surgery. Within 24 hours after discharge from surgery, patients and their parents filled in a 14-item psychometric questionnaire assessing the quality of their recovery. For all questions, a visual analogue scale (VAS) (0-10) was used. MAIN OUTCOME MEASURE: Patients' experience of shortened hospitalization in relation to secondary bone grafting of alveolar defects. Factors influencing the overall experience were measured using a VAS scale. RESULTS: A significant correlation between "Information from the hospital" and feeling worried and anxious was found (P = .04). Additionally, the ability to sleep correlated with pain (P = .003) and with nausea (P = .001). CONCLUSIONS: Although this study included a limited number of patients, the findings suggest that treatment of alveolar residual cleft with bone grafting from the mandibular symphyseal region in a day care surgery setting is characterized by very high patient satisfaction.

Clinical manifestations of diffuse large B-cell lymphoma that exhibits initial symptoms in the maxilla and mandible: a single-center retrospective study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classified as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is difficult as the disease causes a diverse range of clinical symptoms with no characteristic imaging findings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL that exhibits initial manifestation in the maxilla and mandible. METHODS: Of the 2748 patients with malignant tumors of the oral and maxillofacial region examined at our hospital during a period of 11 years between January 2006 and December 2016, 27 primary cases diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled in this study. Evaluations were based on sex, age, whether treatment was provided by a previous physician, symptoms, duration of disease until treatment was sought, clinical diagnosis, laboratory findings, and imaging results. RESULTS: There were 15 cases that involved the maxilla and 12 that involved the mandible. The median duration of disease until treatment was sought was 60 d (3-450 d). All cases exhibited a tumor or a mass, and hypoesthesia of the chin was confirmed in eight cases wherein the mandible was involved. The clinical stages were stage I in eight cases, stage II in ten cases, and stage IV in nine cases. Serum lactate dehydrogenase (LDH) levels were elevated in 13 of 22 patients. The overall survival rate was 63%. CONCLUSIONS: Symptoms associated with nontender swelling and numbness of the lip or chin in the absence of other findings such as dental infections should raise suspicions about DLBCL. Patients should be provided appropriate imaging and accurate biopsy assessments to improve prognosis.

In-bone protein digestion followed by LC-MS/MS peptide analysis as a new way towards the routine proteomic characterization of human maxillary and mandibular bone tissue in oral surgery.

Proteomic characterization of alveolar bones in oral surgery represents an analytical challenge due to their insoluble character. The implementation of a straightforward technique could lead to the routine use of proteomics in this field. This work thus developed a simple technique for the characterization of bone tissue for human maxillary and mandibular bones. It is based on the direct in-bone tryptic digestion of proteins in both healthy and pathological human maxillary and mandibular bone samples. The released peptides were then identified by the LC-MS/MS. Using this approach, a total of 1120 proteins were identified in the maxillary bone and 1151 proteins in the mandibular bone. The subsequent partial least squares-discrimination analysis (PLS-DA) of protein data made it possible to reach 100% discrimination between the samples of healthy alveolar bones and those of the bone tissue surrounding the inflammatory focus. These results indicate that the in-bone protein digestion followed by the LC-MS/MS and subsequent statistical analysis can provide a deeper insight into the field of oral surgery at the molecular level. Furthermore, it could also have a diagnostic potential in the differentiation between the proteomic patterns of healthy and pathological alveolar bone tissue. Data are available via ProteomeXchange with the identifier PXD026775.

Dental effects of enzyme replacement therapy in case of childhood-type hypophosphatasia.

BACKGROUND: Hypophosphatasia (HPP), a skeletal disease characterized by hypomineralization of bone and teeth, is caused by an ALPL gene mutation that leads to low activity of the tissue non-specific alkaline phosphatase enzyme. Although enzyme replacement therapy (ERT) was recently introduced for affected patients, no known studies have been reported regarding its dental effects related to permanent teeth and jaw bones. In the present study, we examined the dental effects of ERT in a case of childhood-type hypophosphatasia, including panoramic radiography findings used to estimate the dental age of permanent teeth and mandibular bone density. Furthermore, the effects of that therapy on the periodontal condition of the patient were evaluated by comparing periodontal pocket depth before and after initiation. CASE PRESENTATION: An 11-year-1-month-old boy was referred to our clinic for consultation regarding oral management. Two primary incisors had spontaneously exfoliated at 1 year 8 months old and he had been diagnosed with childhood-type HPP at the age of 2 years 2 months. Obvious symptoms were localized in the dental region at the time of diagnosis, though later extended to other parts of the body such as bone pain. ERT was started at 11 years 7 months of age, after which bone pain disappeared, and motor functions and activities of daily living improved. We estimated dental age based on tooth development stage. The age gap between chronological and dental ages was expanded before treatment, and then showed a constant decrease after ERT initiation and finally disappeared. The index for mandibular bone density (mandibular cortical width / length from mesial buccal cusp to apex of first molar) was increased after ERT initiation. Furthermore, the periodontal condition for all teeth except those exfoliated was stable after starting therapy. CONCLUSIONS: ERT resulted in improved tooth and mandibular bone mineralization, with notably good effects on teeth under formation. Acceleration of mineralization of roots associated with erupting teeth leads to stabilization of the periodontal condition. We concluded that ERT contributed to the improved dental condition seen in this patient.

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.

Probiotics protect against tenofovir-induced mandibular bone loss in mice by rescuing mandible-derived mesenchymal stem cell proliferation and osteogenic differentiation.

BACKGROUND: Tenofovir disoproxil fumarate (TDF), a primary antiretroviral agent used to treat AIDS, triggers systematic bone loss. However, the effect of TDF on osteopenia or osteoporosis in the jaw remains unclear. TDF-induced bone loss in the jaw, if any, likely involves mandible-derived mesenchymal stem cells (MMSCs), which play a key role in jawbone metabolism. Probiotics prevent long bone loss, and could prove efficacious in treating TDF-induced mandibular bone loss. OBJECTIVES: To determine whether TDF triggers mandibular bone loss, elucidate the underlying mechanisms, and study the effect of Lactobacillus rhamnosus GG (LGG) on TDF-induced bone loss in the jaw. METHODS: Tenofovir disoproxil fumarate was administered orally daily and LGG semiweekly from eight weeks to the end of the study (LGG group) to male C57BL6/J mice. The mice were sacrificed, and body weight (BW) and serum Ca and P were measured. Mandibular histomorphometry was evaluated by micro-CT. MMSCs and LGG culture supernatants were isolated, and MMSC proliferation and ALP production when treated with different concentrations of LGG supernatant and/or TDF were measured. Relative abundance of osteogenic markers was assessed by qPCR. RESULTS: Orally administered LGG protected against bone mass loss and deterioration of bone microarchitecture and increased serum P levels. The BW of the TDF group was highest among the study groups. TDF partially impaired osteogenesis and proliferation of MMSCs. LGG culture supernatant rescued MMSC osteogenesis and proliferation, and osteogenic gene expression. CONCLUSIONS: Lactobacillus rhamnosus GG protected against tenofovir-induced mandibular bone loss in mice by rescuing MMSC proliferation and osteogenesis.

Plasma Osteocalcin Levels, Status of Oral Disease and Alteration in Mandibular Bone Density in Postmenopausal Women.

AIM: The present study was undertaken for assessing plasma osteocalcin levels, status of oral disease, and alteration in mandibular bone density in postmenopausal women (PMW). MATERIALS AND METHODS: In all, 80 premenopausal women and 80 PMW were enrolled. For analyzing the oral dryness, clinical score of oral dryness (CSOD) on a scale of up to 10 was used. Complete dental profiling of all the patients was done. Digital panoramic radiographs were taken for all the patients. Bone mineral density (BMD) was evaluated by measuring the following parameters: mandibular cortical index (MCI), panoramic mandibular index (PMI), mandibular cortical width (MCW), and fractal dimension (FD). Osteocalcin levels were evaluated with enzyme-linked immunosorbent assay technique. All the results were recorded and analyzed. RESULTS: Mean osteocalcin levels of PMW (453.12 ng/mL) were significantly higher in comparison to the premenopausal women (249.28 ng/mL). Postmenopausal women had significantly higher CSOD and number of peri-apical radiolucencies in comparison to premenopausal women. Bone mineral density as assessed by MCI was found to be negatively and significantly correlated with oral disease status and osteocalcin levels. Significant difference was obtained while comparing the MCI inbetween the two study groups. CONCLUSION: There is significantly higher prevalence of oral lesions along with oral dryness in postmenopausal women. Also, thinning of mandibular cortex is significantly higher in postmenopausal women. Higher plasma osteocalcin levels help in predicting osteopenia/osteoporosis at an early stage in such patients. CLINICAL SIGNIFICANCE: In PMW, special considerations should be made while planning for dental implant therapy.

Tissue regeneration during lower jaw restoration in zebrafish shows some features of epimorphic regeneration.

Zebrafish have the ability to regenerate skeletal structures, including the fin, skull roof, and jaw. Although fin regeneration proceeds by epimorphic regeneration, it remains unclear whether this process is involved in other skeletal regeneration in zebrafish. Initially in epimorphic regeneration, the wound epidermis covers the wound surface. Subsequently, the blastema, an undifferentiated mesenchymal mass, forms beneath the epidermis. In the present study, we re-examined the regeneration of the zebrafish lower jaw in detail, and investigated whether epimorphic regeneration is involved in this process. We performed amputation of the lower jaw at two different positions; the proximal level (presence of Meckel's cartilage) and the distal level (absence of Meckel's cartilage). In both manipulations, a blastema-like cellular mass was initially formed. Subsequently, cartilaginous aggregates were formed in this mass. In the proximal amputation, the cartilaginous aggregates were then fused with Meckel's cartilage and remained as a skeletal component of the regenerated jaw, whereas in the distal amputation, the cartilaginous aggregates disappeared as regeneration progressed. Two molecules that were observed during epimorphic regeneration, Laminin and msxb, were expressed in the regenerating lower jaw, although the domain of msxb expression was out of the main plain of the aggregate formation. Administration of an inhibitor of Wnt/ß-catenin signaling, a pathway associated with epimorphic regeneration, showed few effects on lower jaw regeneration. Our finding suggests that skeletal regeneration of the lower jaw mainly progresses through tissue regeneration that is dependent on the position in the jaw, and epimorphic regeneration plays an adjunctive role in this regeneration.

Mandibular Reconstruction with Free Vascularized Fibular Graft.

An iliac block graft is the most commonly used biomaterial for reconstruction following resection of the mandible. Its use has some disadvantages, however, including limitations on the amount of bone that may be harvested, and the subsequent increase in burden on the iliac bone. Therefore, recently, free vascularized fibular grafts have been used as an alternative in some cases. Here, we report the advantages of, and issues related to reconstruction using free vascularized fibular grafts observed at Tokyo Dental College Chiba Hospital. Eight patients undergoing mandibular reconstruction using free vascularized fibular grafts between January 2003 and January 2017 were investigated. Of these, 6 were men, and 2 were women. Age ranged from 38 to 74 years (average, 54 years). Primary diseases comprised malignant tumor in 3 patients, benign tumor in 3, and radiation osteomyelitis of the mandible in 2. The defects were classified as follows according to the CAT system (Condylar Head, Mandibular Angle, Mental Tubercle): 3 cases of Body, 2 of AT, and 1 case each of TT, ATTA, and CATT. The resection range of the mandible was 5-16 cm (average, 10 cm). The single barrel technique was used in 7 cases, and the double barrel technique in 1. In terms of the flap survival ratio, complete engraftment was achieved in 6 out of the 8 cases. Two cases of radiation osteomyelitis of the mandible, with necrosis caused by vascular breakdown after wound infection, were observed, however. While the advantages of mandibular reconstruction by this method include comparatively safe conditions and functional recovery, there were also some problems. It was inappropriate for cases of radiation osteomyelitis of the mandible; those where anti-inflammatory therapy was ineffective; and those where greater resection of the soft tissue was required. Further study is needed to clarify the criteria for selecting this procedure.

Low-serum culture with novel medium promotes maxillary/mandibular bone marrow stromal cell proliferation and osteogenic differentiation ability.

OBJECTIVES: The purpose of this study was to evaluate the effect of low-serum STK2 medium on the isolation and osteogenic differentiation of human maxillary/mandibular bone marrow stromal cells (MBMSCs). MATERIALS AND METHODS: Human MBMSCs were obtained from patients undergoing dental implant treatment. These cells were cultured in serum-free medium or STK2 medium containing 1  % fetal bovine serum (low-serum) or α-MEM containing 10  % fetal bovine serum (control). Proliferation on the culture surface, cell surface antigen expression, and mRNA levels of neural crest and osteogenic markers were examined. Alkaline phosphatase assay and Alizarin red staining were used to assess osteogenic differentiation potential. Immunoblotting analysis was performed to detect ERK phosphorylation. RESULTS: Low-serum and control MBMSCs were positive for CD73, CD90, and CD105 and negative for CD14, CD34, CD45, CD271, and HLA-DR. CD140a was absent in low-serum cells but present in control cells. Low-serum MBMSCs proliferated more than control MBMSCs. After induction of osteogenic differentiation, alkaline phosphatase activity and osteocalcin mRNA levels were higher in low-serum MBMSCs than in control cells, and Alizarin red staining was stronger in low-serum MBMSCs than in control cells. Low-serum culture promoted ERK phosphorylation. CONCLUSIONS: MBMSCs precultured in low-serum medium exhibited a greater cumulative cell number and a higher osteogenic differentiation capacity than those cultured in control medium. CLINICAL RELEVANCE: These findings indicate that low-serum STK2 culture might be useful to promote MBMSC proliferation and osteogenic differentiation. This method requires less autologous blood collection for cell expansion than conventional methods, thus reducing the burden on patients.

Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair.

We have previously shown that the combined delivery of mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF) and bone morphogenetic protein 6 (BMP-6) induces significantly more bone formation than that induced by the delivery of any single factor or a combination of any two factors. We now determine whether the exogenous addition of VEGF and BMP-6 is sufficient for bone healing when MSCs are not provided. Poly(lactic-co-glycolic acid) (PLAGA) microsphere-based three-dimensional scaffolds (P) were fabricated by thermal sintering of PLAGA microspheres. The scaffolds were chemically cross-linked with 200 ng recombinant human VEGF (P(VEGF)) or BMP-6 (P(BMP-6)) or both (P(VEGF+BMP-6)) by the EDC-NHS-MES method. Release of the proteins from the scaffolds was detected for 21 days in vitro which confirmed their comparable potential to supply the proteins in vivo. The scaffolds were delivered to a critical-sized mandibular defect created in 32 Sprague Dawley rats. Significant bone regeneration was observed only in rats with P(VEGF+BMP-6) scaffolds at weeks 2, 8 and 12 as revealed by micro-computer tomography. Vascular ingrowth was higher in the P(VEGF+BMP-6) group as seen by microfil imaging than in other groups. Trichrome staining revealed that a soft callus formed in P(VEGF), P(BMP-6) and P(VEGF+BMP-6) but not in P. MSCs isolated from rat femurs displayed expression of the bone-specific marker osteocalcin when cultured with P(VEGF), P(BMP-6), or P(VEGF+BMP-6) but not with P. Robust mineralization and increased alkaline phosphatase gene expression were seen in rat MSCs when cultured on P(VEGF+BMP-6) but not on P, P(VEGF), or P(BMP-6). Thus, unlike the delivery of VEGF or BMP-6 alone, the combined delivery of VEGF and BMP-6 to the bone defect significantly enhanced bone repair through the enhancement of angiogenesis and the differentiation of endogenously recruited MSCs into the bone repair site.

Mandibular Symphyseal Bone Graft for Reconstruction of Alveolar Cleft Defects: Volumetric Assessment With Cone Beam Computed Tomography 1-Year Postsurgery.

OBJECTIVE: The aims of this retrospective study were to evaluate the volumetric outcome of mandibular symphyseal bone graft in patients with unilateral cleft lip and palate by estimating the bone fill 1-year postoperatively on cone beam computed tomography. The outcome was assessed in relation to the (1) root development stage of the cleft side canine, (2) presence/absence of a cleft side lateral incisor, and (3) volume size of the preoperative cleft defect. METHODS: The alveolar bone defect volume of 32 consecutive unilateral cleft lip and palate patients aged 8 years 1 month to 11 years 11 months was evaluated using a recently defined and standardized protocol. The outcome was calculated as the percentage of bone fill using the formula (VOLpre - VOLpost) / VOLpre) × 100. RESULTS: The preoperative mean alveolar cleft volume was 934 mm(3), and the average percentage bone fill was 87%. There was no significant difference between bone fill and root developmental stage of the cleft-side canine (P = .882) nor presence/absence of the cleft side lateral incisor (P = .803). The size of the cleft defect did not correlate with the bone fill (r = .03, P = .84). CONCLUSIONS: Secondary alveolar bone grafting with mandibular symphyseal bone graft in patients with unilateral cleft lip and palate is an attractive procedure assessed from the volumetric outcome using cone beam computed tomography. The 1-year average bone fill of 87% was not significantly influenced by root development stage of the cleft-side canine, presence or the absence of a cleft side lateral incisor, or size of the alveolar defect.

Mandibular bone loss in ewe induced by hypothalamic-pituitary disconnection.

PURPOSE: It is supposed that the demographic change will lead to an increase in patients with impaired alveolar bone conditions. Large animal models are of particular interest in this context as they are suitable for developing and testing new dental implants. Recently, we demonstrated that surgical hypothalamo-pituitary disconnection (HPD) causes a pronounced low-turnover situation leading to cortical and trabecular bone loss in sheep. In this study, we aimed to investigate the influence of the HPD procedure on the alveolar bone. METHODS: Ten adult Merino ewes were randomly assigned to two groups: Control and HPD. After 6 months, we analysed the cortical and trabecular bone of all mandibles by histomorphometry and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: HPD ewes showed a significant decrease in cortical thickness by ~20%, a significant increase in cortical porosity by ~20% and a significant decrease in bone volume by ~30% in comparison with Control ewes. CONCLUSION: Our results underline the importance of central regulatory mechanisms of bone turnover. However, further studies are needed to understand these central regulatory elements of bone turnover in detail and to judge the value of the HPD sheep for dental research.

Radiological features of Stafne mandibular bone cavity in panoramic image and cone beam computed tomography.

BACKGROUND: Stafne mandibular bone cavity (SMBC) is an asymptomatic radiolucent lesion observed in the mandible on X-ray images, with well-defined borders. This lesion does not require treatment, and size changes are very rare. The purpose of this article is to summarize the radiological and clinical features of SMBC, aiming to prevent misinterpretation of this benign lesion as other pathologies and aid in differential diagnosis within the field of dental practice. METHODS: A total of 32 patients who visited our hospital and were radiologically diagnosed with SMBC based on cone-beam computed tomography (CBCT) and panoramic images between 2005 and 2021 were included in this study. Among them, surgical intervention was performed in one case. Gender and age distribution of the patients, radiographic location and size of the lesion, relationship with the mandibular canal in CBCT, presence of cortical bone erosion in the mandibular lingual area in panoramic images, and the amount of residual cortical bone on the affected side in CBCT were investigated. RESULT: Patients were 26 men (81.3%) and 6 women, with a mean age of 54.3 years. The average horizontal and vertical length was 16.6 mm and 10.6 mm. Out of a total of 32 cases, 29 cases were found in the posterior region of the mandibular body, while 3 cases were in the angle of the mandible. Lesions located below the mandibular canal were observed in 29 cases, while lesions involving the mandibular canal were present in 3 cases. Erosion of the mandibular lingual cortical bone was observed in 11 cases (34.4%), while 21 cases (65.6%) showed no erosion on panoramic images. Among the total of 14 cases (43.8%) where the cortical bone on the affected side was invaded, the average residual cortical bone thickness was 1.1 mm. CONCLUSION: SMBC is a benign lesion primarily found in the mandibular angle and posterior body of the mandible. In most cases, treatment is not necessary, and differentiation from other lesions can be achieved by understanding its clinical characteristics and features on panoramic radiographs and CBCT.

Challenges in the Assessment of Medullary Bone Invasion in Oral Cavity Cancers and Its Prognostic Significance.

BACKGROUND: As per AJCC 8th edition TNM staging system, bone invasion is a poor prognostic marker that upstages oral cavity squamous carcinoma (OSCC) to pT4a. Cortical erosion alone of bone or tooth socket by a gingival primary is not sufficient to upstage a tumour. The differentiation of cortical erosion from invasion through the cortical bone into the medulla is often challenging, limiting accurate staging. This review aims to assess the difficulties in differentiating cortical erosion from medullary invasion and evaluate the prognostic significance of different patterns of bone involvement. METHODS: A retrospective review of OSCC with primary curative surgery and bone resection treated at a single-center over 10 years, was performed to assess the prognostic significance of bone invasion. Hematoxylin-eosin stained slides of a subset of cases were re-reviewed in a planned manner to assess difficulties in precise categorization (no invasion/erosion/cortical invasion and medullary invasion), evaluate interobserver agreement, and correlate with clinical outcome. RESULTS: Five hundred and ninety patients were included, with a median follow-up of 28 months. On univariate analysis, the 3-year local, nodal and distant metastasis control were not significantly different in the 3 groups of no invasion, erosion, and invasion (p = 0.43, 0.47, and 0.47, respectively). Overall survival (OS) at 3 years was 78.1% and disease-free-survival(DFS) was 63.7% in the entire cohort. On univariate analysis, there was significant difference in OS and DFS based on these groups. This did not translate into independent prognostic benefit on multivariable analysis (p = 0.75 and 0.19, respectively). The independent prognostic factors were margin positivity, tumor differentiation, perineural invasion and pathological nodal involvement. Planned re-review of a subset of 202 cases resulted in a change in bone involvement category in 26/202 cases, which was mainly due to difficulty in assessing cortico-medullary junction near the tooth socket and bone fragmentation. The assessment showed moderate to near complete agreement (kappa 0.59-0.82) between 2 observers. CONCLUSION: Our study shows that bone involvement is not an independent prognostic marker and there is no specific correlation of medullary invasion with outcome over those that showed cortical erosion. Several factors contribute to difficulties and interobserver variability in assessing bone involvement.

Metformin prevents mandibular bone loss in a mouse model of accelerated aging by correcting dysregulated AMPK-mTOR signaling and osteoclast differentiation.

Background: Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1-/- mice displaying accelerated skeletal aging represent a useful model for testing interventions against premature jaw bone loss. As an anti-aging agent, metformin may ameliorate molecular dysfunction driving osteoporosis pathogenesis. We explored the mechanisms of mandibular osteopenia in Bmi1-/- mice and prevention by metformin treatment. Methods: Three mouse groups were utilized: wild-type controls, untreated Bmi1-/-, and Bmi1-/- receiving 1 g/kg metformin diet. Mandibular bone phenotype was assessed by X-ray, micro-CT, histology, and immunohistochemistry. AMPK-mTOR pathway analysis, senescence markers, osteoblast and osteoclast gene expression were evaluated in jaw tissue. Osteoclast differentiation capacity and associated signaling molecules were examined in cultured Bmi1-/- bone marrow mononuclear cells ± metformin. Results: Bmi1 loss reduced mandible bone density concomitant with decreased AMPK activity, increased mTOR signaling and cellular senescence in jaw tissue versus wild-type controls. This was accompanied by impaired osteoblast function and upregulated osteoclastogenesis markers. Metformin administration normalized AMPK-mTOR balance, oxidative stress and senescence signaling to significantly improve mandibular bone architecture in Bmi1-/- mice. In culture, metformin attenuated excessive osteoclast differentiation from Bmi1-/- marrow precursors by correcting dysregulated AMPK-mTOR-p53 pathway activity and suppressing novel pro-osteoclastogenic factor Stfa1. Conclusions: Our study newly demonstrates metformin prevents accelerated jaw bone loss in a premature aging murine model by rectifying molecular dysfunction in cellular energy sensors, redox state, senescence and osteoclastogenesis pathways. Targeting such age-associated mechanisms contributing to osteoporosis pathogenesis may help maintain oral health and aesthetics in the growing elderly population. Translational potential: The pronounced mandibular osteopenia exhibited in Bmi1-/- mice represents an accelerated model of jaw bone deterioration observed during human aging. Our finding that metformin preserves mandibular bone integrity in this progeroid model has important clinical implications. As an inexpensive oral medication already widely used to manage diabetes, metformin holds translational promise for mitigating age-related osteoporosis. The mandible is essential for chewing, swallowing, speech and facial structure, but progressively loses bone mass and strength with advancing age, significantly impacting seniors' nutrition, physical function and self-image. Our results suggest metformin's ability to rectify cellular energy imbalance, oxidative stress and osteoclast overactivity may help maintain jaw bone health into old age. Further research is still needed given metformin's multifaceted biology and bone regulation by diverse pathways. However, this preclinical study provides a strong rationale for clinical trials specifically examining mandibular outcomes in elderly subjects receiving standard metformin treatment for diabetes or prediabetes. Determining if metformin supplementation can prevent or delay oral disability and disfigurement from senescent jaw bone loss in the growing aged population represents an important public health priority. In summary, our mechanistic findings in a genetic mouse model indicate metformin merits investigation in rigorous human studies for alleviating morbidity associated with age-related mandibular osteoporosis.

Enhanced bone formation of rat mandibular bone defects with collagen membranes loaded on bone morphogenetic protein-9.

Background/purpose: Bone morphogenetic protein-9 (BMP-9) has demonstrated multiple advantages in promoting osteogenesis. Our previous findings have indicated that the use of an absorbable collagen membrane (ACM) as a carrier for growth factors is effective in stimulating bone regeneration. The objective of this study was to assess the synergistic impact of BMP-9 incorporated into ACM (ACM/BMP-9) on bone formation within rat mandibular bone defects. Materials and methods: Circular bone defects of critical size were surgically induced on both sides of the rat mandibular bone, with subsequent random allocation into distinct groups: control, ACM alone, and ACM loaded with low (0.5 µg) or high (2.0 µg) concentrations of BMP-9. We conducted real-time in vivo micro-computerized tomography scans at the baseline and at 2, 4, and 6 weeks, and measured the volume of newly formed bone (NFB), bone mineral density (BMD) of NFB, and the closure percentage of the NFB area. Histological and histomorphometric analyses were performed at 6 weeks. Results: Real-time assessment revealed notably higher levels of bone volume, BMD, and closure percentage in the NFB area for the groups treated with ACM/BMP-9 compared to the control and ACM groups. Within the high concentration of BMP-9 group, the volume and BMD of NFB exhibited a significant increase at 6 weeks compared to baseline. Histological examination confirmed the existence of osteoblasts, osteocytes, and blood vessels within the NFB. Conclusion: Considering the limitations of this research, the real-time evaluation finding indicates that ACM/BMP-9 effectively promotes bone formation in critical-size mandibular defects in rats.

Customized bioceramic scaffolds and metal meshes for challenging large-size mandibular bone defect regeneration and repair.

Large-size mandible graft has huge needs in clinic caused by infection, tumor, congenital deformity, bone trauma and so on. However, the reconstruction of large-size mandible defect is challenged due to its complex anatomical structure and large-range bone injury. The design and fabrication of porous implants with large segments and specific shapes matching the native mandible remain a considerable challenge. Herein, the 6% Mg-doped calcium silicate (CSi-Mg6) and ß- and α-tricalcium phosphate (ß-TCP, α-TCP) bioceramics were fabricated by digital light processing as the porous scaffolds of over 50% in porosity, while the titanium mesh was fabricated by selective laser melting. The mechanical tests showed that the initial flexible/compressive resistance of CSi-Mg6 scaffolds was markedly higher than that of ß-TCP and α-TCP scaffolds. Cell experiments showed that these materials all had good biocompatibility, while CSi-Mg6 significantly promoted cell proliferation. In the rabbit critically sized mandible bone defects (∼13 mm in length) filled with porous bioceramic scaffolds, the titanium meshes and titanium nails were acted as fixation and load bearing. The results showed that the defects were kept during the observation period in the blank (control) group; in contrast, the osteogenic capability was significantly enhanced in the CSi-Mg6 and α-TCP groups in comparison with the ß-TCP group, and these two groups not only had significantly increased new bone formation but also had thicker trabecular and smaller trabecular spacing. Besides, the CSi-Mg6 and α-TCP groups showed appreciable material biodegradation in the later stage (from 8 to 12 weeks) in comparison with the ß-TCP scaffolds while the CSi-Mg6 group showed much outstanding mechanical capacity in vivo in the early stage compared to the ß-TCP and α-TCP groups. Totally, these findings suggest that the combination of customized strength-strong bioactive CSi-Mg6 scaffolds together with titanium meshes is a promising way for repairing the large-size load-bearing mandible defects.