Daigo Yoshiga

Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia

We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line–derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.

The dual function of hepatic SOCS3 in insulin resistance in vivo

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro‐inflammatory cytokines, such as TNFα and IL‐6, has been implicated in inflammation‐mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte‐specific SOCS3‐deficient (L‐SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L‐SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti‐inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L‐SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute‐phase proteins were elevated in L‐SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.

Sprouty2 controls proliferation of palate mesenchymal cells via fibroblast growth factor signaling.

Cleft palate is one of the most common craniofacial deformities. The fibroblast growth factor (FGF) plays a central role in reciprocal interactions between adjacent tissues during palatal development, and the FGF signaling pathway has been shown to be inhibited by members of the Sprouty protein family. In this study, we report the incidence of cleft palate, possibly caused by failure of palatal shelf elevation, in Sprouty2-deficient (KO) mice. Sprouty2-deficient palates fused completely in palatal organ culture. However, palate mesenchymal cell proliferation estimated by Ki-67 staining was increased in Sprouty2 KO mice compared with WT mice. Sprouty2-null palates expressed higher levels of FGF target genes, such as Msx1, Etv5, and Ptx1 than WT controls. Furthermore, proliferation and the extracellular signal-regulated kinase (Erk) activation in response to FGF was enhanced in palate mesenchymal cells transfected with Sprouty2 small interfering RNA. These results suggest that Sprouty2 regulates palate mesenchymal cell proliferation via FGF signaling and is involved in palatal shelf elevation.

Zoledronic Acid Enhances Lipopolysaccharide-Stimulated Proinflammatory Reactions through Controlled Expression of SOCS1 in Macrophages

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of nitrogen-containing bisphosphonate (NBP) use. Many studies have shown that BRONJ is limited to the jawbone and does not occur in the other bones. We hypothesized that BRONJ is related to local bacterial iections and involves the innate immune system. To examine the relationship between BRONJ and innate immunity, we examined the effects of NBPs on macrophages, one of the important cell types in innate immunity. The expression of toll-like receptor-4 (TLR4) in cells after pretreatment with zoledronic acid (ZOL) did not considerably differ from that in untreated control cells. However, cytokine levels and nitric oxide (NO) production increased after pretreatment with ZOL. Furthermore, ZOL induced NF-κB activation by enhancing IκB-α degradation. Lipopolysaccharide (LPS)-induced apoptosis also increased after pretreatment with ZOL. This effect was mediated by a reduction of suppressor of cytokine signaling-1 (SOCS1), which is a negative regulator of myeloid differentiation primary response gene 88 (MyD 88)-dependent signaling. These results suggest that ZOL induced excessive innate immune response and proinflammatory cytokine production and that these processes may be involved in the bone destruction observed in BRONJ.

Clinical comparison between the retromandibular approach for reduction and fixation and endoscope-assisted open reduction and internal fixation for mandibular condyle fractures.

Objective Endoscope-assisted transoral open reduction and internal fixation (EAORIF) for mandibular condyle fractures has recently become popular because it is minimally invasive, provides excellent visibility without a large incision, and reduces surgical scarring and the risk of facial nerve injury. This report describes a retrospective clinical study that compared certain clinical parameters, including postoperative function, between the retromandibular (RM) approach and EAORIF. Methods Fifteen patients were treated by the RM approach, whereas 15 underwent EAORIF between July 2006 and September 2011 at Kyushu Dental College, Japan. Clinical indices comprised fracture line, fracture type, number of plates used, surgical duration, bleeding amount, and functional items, including maximum interincisal opening, mandibular deviation on the opening pathway, malocclusion, facial paresthesia, and temporomandibular joint pain and clicking. Results The areas subjected to either approach included lower neck and subcondyle. The RM approach was used for mandibular condyle fractures with dislocation of a small bone segment. Both groups used 2 plates in all cases. Surgical duration, maximum interincisal opening, mandibular deviation, occlusion, and temporomandibular joint function at 6 months after surgery were comparable between groups. The average bleeding amount in the EAORIF group was greater than in the RM group. One patient from the RM group developed facial paresthesia that persisted for 6 months after surgery. Conclusions It was concluded that surgical treatment was suitable for fractures of the lower neck and subcondylar. Both procedures showed good results in the functional items of this study.

Prognosis factors in the treatment of bisphosphonate-related osteonecrosis of the jaw - Prognostic factors in the treatment of BRONJ.

Objectives: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a relatively rare but serious side effect of bisphosphonate (BP)-based treatments. This retrospective study aimed to investigate the risk factors and predictive markers in cases where patients were refractory to a recommended conservative treatment offered in our hospital. Patients and Methods: This single-center study collated the medical records of all patients treated for BRONJ between 2004 and 2011. A complete medical history, including detailed questionnaires, was collected for all patients, focusing on identifying underlying risk factors, clinical features, location and bone marker levels of BRONJ. Results: The mean BRONJ remission rate was 57.6%, and the median duration of remission was seven months. Eighteen patients (34.6%) had persistent or progressive disease with a recommended conservative treatment for BRONJ. Notably, urinary cross-linked N-terminal telopeptide of type 1 collagen (NTX) levels in those resistant to conservative treatment tended to be lower than in patients that healed well. Conclusions: We confirm that a significant proportion of BRONJ sufferers are refractory to a recommended conservative treatment and find that anticancer drugs, periodontal disease, the level of bone exposure and the dosage of intravenous BPs (e.g. zoledronate) represent specific risk factors in BRONJ that may determine the success of a recommended conservative treatment. Additionally, the NTX levels might be able to be a prognostic factor for the conservative treatment of BRONJ; additional research is necessary. Key words:Bisphosphonate, osteonecrosis, jaw, prognostic, retrospective.

Evaluation of mandibular reconstruction with particulate cancellous bone marrow and titanium mesh after mandibular resection due to tumor surgery.

There are numerous treatment modalities for mandibular defects after tumor surgery. Autogenous particulate cancellous bone marrow graft combined with titanium mesh (PCBM-MESH) is an alternative procedure. The purpose of this study was to evaluate PCBM-MESH for mandibular reconstruction. There were a total of 10 cases from 2000 to 2011. Mandibles were successfully reconstructed in 9 cases; however, reconstruction failed in 1 case. Overall, the recovery of facial contours was excellent; conversely, the evaluation of prosthetic treatment varied widely. Thus, we suggest 3 steps for mandibular reconstruction: (1) recover the continuity of bone segments; (2) simulate optimum facial contours and dental occlusion; and (3) perform the occlusion with dental prostheses. PCBM-MESH is a valuable method for mandibular defects—particularly for restoring facial contours and a favorable alveolar ridge.

Increased Levels of Interleukin-6 in Synovial Lavage Fluid From Patients With Mandibular Condyle Fractures: Correlation With Magnetic Resonance Evidence of Joint Effusion

PURPOSE The aim of the present study was to investigate the relation between magnetic resonance (MR) evidence of joint effusion and concentrations of proinflammatory cytokines, including interleukin (IL)-1β and IL-6, in washed-out synovial fluid samples obtained from patients with mandibular condyle fractures. PATIENTS AND METHODS Twenty-five joints in 23 patients with mandibular condyle fractures were examined. Computed tomography was used to determine the position of the fracture and MR examination was performed in all cases. Twenty-five joints underwent temporomandibular joint (TMJ) irrigation before surgical treatment for the fractures. The detection rates and concentrations of the tested cytokines were determined, and their relations to evidence of joint effusion and positions of the condylar fractures were analyzed. RESULTS Six TMJ fractures were found in the head, 10 in the upper neck, 4 in the lower neck, and 5 in the subcondyle. MR evidence of joint effusion was observed in 17 of 25 TMJs (68.0%). The detection rate and concentration of IL-6 were significantly higher in patients with MR evidence of joint effusion and those with high condylar fractures. Moreover, there was a correlation between joint effusion grade and IL-6 concentration. CONCLUSIONS The present findings showed a correlation between MR evidence of joint effusion and concentration of IL-6 in washed-out synovial fluid samples collected from patients with mandibular condyle fractures. These results may provide support for arthrocentesis as a reasonable treatment modality for high condylar fractures.

Erratum to: Intraoperative detection of viable bone with fluorescence imaging using Visually Enhanced Lesion Scope in patients with bisphosphonate-related osteonecrosis of the jaw: clinical and pathological evaluation.

There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ), because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce how to provide preoperative labeling of the viable bone with minocycline bone fluorescence technique (MBFT) by using VELscope® and investigate histopathologically. The American Association of Oral and Maxillofacial Surgeons (AAOMS) and the Japanese Society of Oral and Maxillofacial Surgeons (JSOMS) now recommend a more conservative treatment strategy. There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ) because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce a mechanism providing preoperative labeling of a viable bone using minocycline bone fluorescence technique (MBFT) with VELscope® and to histopathologically investigate. This report describes a surgical technique used in six patients with BRONJ who underwent jawbone resection under minocycline bone fluorescence imaging using VELscope®. Subsequently, we investigated and compared the clinical findings using VELscope® and histopathological findings. Histopathological examinations showed that the non-fluorescent moiety was consistent with the BRONJ lesions. The surgical treatments that were exactly performed using MBFT with VELscope® offered successful management of BRONJ. This bone fluorescence helped to define the margins of resection, thus improving surgical therapy for extended osteonecrosis.

Case of mucoepidermoid carcinoma of the sublingual gland accompanied with extensive dystrophic calcification and intratumoral bone formation

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Although the histopathological findings are diverse, no case of salivary MEC accompanied with bone formation has been reported. Herein, we present the first case of MEC with intratumoral bone formation.