Congenital Upper Lip Sinus.

Congenital upper lip sinus (CULS) is an extremely rare anomaly. The aim of the study is to present a new case and compile the present knowledge of CULS to help foster a deeper understanding of this disease. A 9-year-old girl with a midline CULS, a prolonged maxillary labial frenulum, and a palatal epulis is presented. Thirty-nine papers met the eligibility criteria and 45 cases were included in the systematic review. CULS shows typical clinical and pathologic characteristics. It tends to occur at the midline region horizontally (n=35; 78%) and the upper part of the white lip (n=23; 51%) vertically. No ethnic predilection is found, but it tends to show a female predilection (n=28; 62%). Twenty-six cases (58%) are symptomatic. Thirteen cases (29%) are accompanied by other maxillofacial defects. In all cases, the sinus was lined with stratified squamous epithelium. The etiology remains unknown but 3 theories have been put forward: the fusion theory, the merging theory, and the invagination theory. The authors believe that CULS shows homogeneity with cleft lip to some extent and maybe a microform of it. Primary treatment is surgical excision and the prognosis is favorable, with no complications or recurrence.

Exploring the relations of NLR, hsCRP and MCP-1 with type 2 diabetic kidney disease: a cross-sectional study.

Type 2 diabetic kidney disease (T2DKD) is a common microvascular complication of type 2 diabetes mellitus (T2DM), and its incidence is significantly increasing. Microinflammation plays an important role in the development of T2DKD. Based on this, this study investigated the value of inflammatory markers including neutrophil-lymphocyte ratio (NLR), high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1) in the prediction of T2DKD. This was a cross-sectional survey study. A total of 90 patients with T2DM, who were hospitalized in the nephrology and endocrinology departments of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from June 2021 to January 2022, were included and divided into three groups (A1, A2, A3) according to the urinary albumin-to-creatinine ratio (UACR). Observe and compare the basic information, clinical and laboratory data, and the inflammatory markers NLR, hs-CRP, MCP-1. Results revealed that high levels of NLR (OR = 6.562, 95% CI 2.060-20.902, P = 0.001) and MCP-1 (OR = 1.060, 95% CI 1.026-1.095, P < 0.001) were risk factors in the development of T2DKD. Receiver operating characteristic curve analysis showed that the area under curve of NLR and MCP-1 in diagnosing T2DKD were 0.760 (95% CI 0.6577-0.863, P < 0.001) and 0.862 (95% CI 0.7787-0.937, P < 0.001). Therefore, the inflammatory markers NLR and MCP-1 are risk factors affecting the development of T2DKD, which of clinical value may be used as novel markers of T2DKD.

Donor-site morbidity of free fibula flap in pediatric patients: A systematic review and meta-analysis.

The morbidity of free fibula flap (FFF) in pediatric patients has gained attention. Thus, we aimed to evaluate donor-site morbidity after FFF harvesting in pediatric patients and its relationship with age. A systematic literature search of databases for cross-sectional studies related to pediatric donor-site morbidity after FFF harvesting was performed. Two independent reviewers evaluated relevant article titles and abstracts to extract data regarding donor-site morbidity from each article. Fifteen studies were included in the meta-analysis that evaluated the rate of complications. Individual cases of ankle instability were divided into the 0-13- and 13-17-year-old groups. The Chi-square test was used to compare ankle instability between both groups. A logistic regression model was created to analyze the relationships between age and ankle instability/claw toe. Sixteen English articles published between 2007 and 2021 were included in the systematic review. Information on morbidities of 294 cases in which FFF was used was collected. The mean incidence rate of complications, instability, claw toe, and nerve injury were 19.3%, 12.9%, 5.9%, and 5.1%, respectively. Bivariate analysis showed that age was significantly correlated with the incidence of ankle instability but not with the incidence of claw toe. The Chi-square test showed that the incidence rate of ankle instability between the age groups was significantly different. Therefore, we recommend 14 years of age as a new predictive factor for ankle instability. Nevertheless, there is limited evidence in this field, and more pediatric research is needed to clarify these findings.

Improving masticatory and swallowing ability of postoperative oral and maxillofacial tumor patients by telerehabilitation-A randomized controlled trial.

OBJECTIVE: To evaluate the effect of telerehabilitation on oral function of oral and maxillofacial tumor patients. DESIGN: Unicentral, single-blind, randomized controlled trial. SETTING: Community. SUBJECTS: Patients with primary oral and maxillofacial tumor receiving surgical treatment. INTERVENTIONS: Telerehabilitation guidance from therapists. MAIN MEASURES: At the beginning of training (T0) and 1 month (T1), 3 months (T2) and 6 months (T3) after training, patients' masticatory ability (mastication efficiency-masticatory performance evaluating gum, maximum bite force and mouth opening) and swallowing ability (water swallowing test) was measured. Modified Sato questionnaire and MD Anderson dysphagia inventory (MDADI) were used for self-evaluation of masticatory and swallowing ability. RESULTS: A total of 64 participants (intervention: 33; control: 31) were included. The masticatory efficiency scores of the intervention group were significantly better than those of the control group at T2 (intervention: 3.67 (0.48); control: 3.03 (0.85)) and T3 (intervention: 4.20 (0.30); control: 3.50 (0.79)); and maximum mouth opening was better at T2 (intervention: 3.18 (0.59); control: 2.77 (0.54)) and T3 (intervention: 3.54 (0.58); control: 3.09 (0.41)). In water swallowing test, the intervention group had better scores at T2 and T3. The scores of MDADI scale in intervention group were better than those in the control group after 3 months of training. In subgroup analysis, the intervention group of oral cancer patients had better swallowing function at T2 and T3, but no significant difference was found in the subgroup of oropharyngeal cancer. CONCLUSIONS: Telerehabilitation could greatly improve the long-term (3-6 months) training effect under the condition of greatly saving medical resources and reducing personnel contact.

Diabetic cardiomyopathy: Clinical phenotype and practice.

Diabetic cardiomyopathy (DCM) is a pathophysiological condition of cardiac structure and function changes in diabetic patients without coronary artery disease, hypertension, and other types of heart diseases. DCM is not uncommon in people with diabetes, which increases the risk of heart failure. However, the treatment is scarce, and the prognosis is poor. Since 1972, one clinical study after another on DCM has been conducted. However, the complex phenotype of DCM still has not been fully revealed. This dilemma hinders the pace of understanding the essence of DCM and makes it difficult to carry out penetrating clinical or basic research. This review summarizes the literature on DCM over the last 40 years and discusses the overall perspective of DCM, phase of progression, potential clinical indicators, diagnostic and screening criteria, and related randomized controlled trials to understand DCM better.

Specificity protein 1/microRNA-92b forms a feedback loop promoting the migration and invasion of head and neck squamous cell carcinoma.

In this study we report a novel specificity protein 1 (SP1)/microRNA-92b (miR-92b) feedback loop regulating the migration and invasion of head and neck squamous cell carcinoma (HNSCC). Microarray and real-time Polymerase Chain Reaction (PCR) were used to detect gene expression in HNSCC tissues and cell lines. Transwell migration, invasion, wound healing and cell counting kit - 8 (CCK-8) cell assays were used to compare cell migration, invasion and proliferation abilities. Chromatin Immunoprecipitation (ChIP) assays were used to detect SP1 binding to the miR-92b promoter. Western blot was used to detect protein levels. An in vivo tumorigenesis experiment was used to evaluate the effect of SP1 knockdown on tumor growth and protein levels were evaluated by immunohistochemistry. We found that the miR-92b expression level was elevated in HNSCC primary focus tissue compared with adjacent normal tissue, and a higher level of miR-92b was related to a higher clinical stage and worse prognosis of HNSCC patients. MiR-92b and SP1 mutually promoted each expression and cooperatively facilitated the migration, invasion and proliferation of HNSCC cells. A decreased level of SP1/miR-92b resulted in a restraint of in vivo tumor growth. In conclusion, our results suggest that the SP1/miR-92b feedback loop generally promotes HNSCC invasion and metastasis, thus presenting a possible therapeutic target in the treatment of HNSCC patients.

Early childhood traffic-related air pollution and risk of allergic rhinitis at 2-4 years of age modification by family stress and male gender: a case-control study in Shenyang, China.

BACKGROUND: Few studies have explored the modifications by family stress and male gender in the relationship between early exposure to traffic-related air pollution (TRAP) and allergic rhinitis (AR) risk in preschool children. METHODS: We conducted a case-control study of 388 children aged 2-4 years in Shenyang, China. These children AR were diagnosed by clinicians. By using measured concentrations from monitoring stations, we estimated the exposures of particulate matter less than 10 µm in diameter (PM10), nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO), and sulfur dioxide (SO2) in preschool children aged 2-4 years. After adjusted potential confounding factors, we used logistic regression model to evaluate the odds ratio (OR) and 95% confidence interval (CI) for childhood AR with exposure to different air pollutants according to the increasing of the interquartile range (IQR) in the exposure level. RESULTS: The prevalence of AR in children aged 2-4 years (6.4%) was related to early TRAP exposure. With an IQR (20 µg/m3) increase in PM10 levels, an adjusted OR was significantly elevated by 1.70 (95% CI, 1.19 to 2.66). Also, with an IQR (18 µg/m3) increase in NO2, an elevated adjusted OR was 1.85 (95% CI, 1.52 to 3.18). Among children with family stress and boys, PM10 and NO2 were positively related to AR symptoms. No significant association was found among children without family stress and girls. CONCLUSIONS: Family stress and male gender may increase the risk of AR in preschool children with early exposure to PM10 and NO2.

Impact of wound closure on fibular donor-site morbidity: a meta-analysis.

BACKGROUND: Vascularized free fibular flaps have been the "workhorses" for reconstruction of many kinds of bone defects. Nevertheless, there is no consensus regarding the optimal wound closure method for fibular donor sites. This study aimed to compare prognostic outcomes of primarily closures (PC) and skin grafts (SG) for fibular donor sites. METHODS: Studies regarding donor-site outcomes of PC versus SG in patients undergoing free fibular flap procedures were included. Two authors individually searched PubMed, Web of Science, EMBASE, Cochrane Library and clinicaltrials.gov up to February 2019, extracted the data and assessed quality of each selected article. Ultimately, The incidences of donor-site morbidities were evaluated. RESULTS: Five studies with a total of 119 patients were included in our analysis. No significant differences were found with respect to the rates of donor-site problems between the PC and SG groups. CONCLUSIONS: Fibular flap patients undergoing PC and SG wound closures may have similar donor-site outcomes. Additional large-scale studies are necessary to draw a solid conclusion.

Hsa-let-7e-5p Inhibits the Proliferation and Metastasis of Head and Neck Squamous Cell Carcinoma Cells by Targeting Chemokine Receptor 7.

This study aimed at determining the role of hsa-let-7e-5p in the progression of head and neck squamous cell carcinoma (HNSCC). The relative levels of hsa-let-7e-5p transcripts in 15 paired of HNSCC and adjacent non-tumor tissues and cells were examined by quantitative real-time PCR (qRT-PCR). The potential targets of hsa-let-7e-5p were predicted and validated by luciferase assay. The impact of altered hsa-let-7e-5p expression on HNSCC cell proliferation and metastasis was determined by CCK-8, wound healing, transwell migration and invasion assays. The effect of hsa-let-7e-5p over-expression on the growth of HNSCC was examined in vivo. Hsa-let-7e-5p expression was significantly down-regulated in HNSCC tissues and highly metastatic PCI-37B cells. Bioinformatic analysis predicted that hsa-let-7e-5p bound to the 3'untranslated region (3'UTR) of chemokine receptor 7(CCR7), which was validated by luciferase assay. While transfection with hsa-let-7e-5p mimic significantly decreased CCR7 protein expression, transfection with hsa-let-7e-5p inhibitor increased CCR7 protein expression in HNSCC cells. Similarly, hsa-let-7e-5p over-expression inhibited PCI-37B cell proliferation, wound healing, migration and invasion, while inhibition of endogenous hsa-let-7e-5p had opposite effects in PCI-37A cells. Hsa-let-7e-5p over-expression inhibited PCI-37B tumor growth in vivo. Therefore, hsa-let-7e-5p acts as a tumor suppressor to inhibit the progression of HNSCC by targeting CCR7 expression. Hsa-let-7e-5p and CCR7 may be therapeutic targets of HNSCC.

Management and prognosis of cancers in the accessory parotid gland.

OBJECTIVE: This study was performed to analyze the clinical management of accessory parotid gland (APG) cancer and possible risk factors for disease-related death. METHODS: Patients diagnosed with primary APG cancers in the largest medical center in Northeast China were enrolled from January 1990 to December 2016. RESULTS: All 43 patients underwent resection of the tumors and superficial parotid gland by a standard Blair incision. Seven (16.3%) patients also required selective neck dissection. The most common lesion was mucoepidermoid carcinoma. Temporary facial paralysis occurred in 11 (25.6%) patients, and permanent facial paralysis occurred in 3 (7.0%) patients because of surgical resection of the facial nerve, which was involved with the tumor. The 5- and 10-year disease-specific survival rates were 86.0% and 66.0%, respectively. The tumor stage, neck status, neck dissection, and tumor grade were significantly associated with disease-related death, but only the tumor grade was an independent risk factor. CONCLUSION: Superficial parotidectomy is a reliable surgical procedure associated with a high survival rate and low morbidity in treating APG cancers. The tumor grade is the key prognostic factor.

Congenital Loss of Permanent Teeth in a Patient With Congenital Insensitivity to Pain With Anhidrosis due to 2 Novel Mutations in the NTRK1 Gene.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, is an extremely rare autosomal recessive disorder. This study investigated the oral and craniofacial manifestations of a 7-year-old Chinese boy affected by CIPA and identified 2 novel mutations in the NTRK1 gene, and a new feature of the disorder was identified. The patient had typical features, including insensitivity to pain, anhidrosis, and mental retardation; recurrent fractures and osteoporosis also were noted. His oral and craniofacial manifestations included congenital blepharoptosis, a large number of missing teeth, serious tooth abrasion, severe soft tissue injuries, and dental caries. Radiographic examination showed congenital loss of the permanent tooth germs, thin and weak alveolar bone of the mandible, and a fracture of the right mandible. This study extends the spectrum of NTRK1 mutations observed in patients with a diagnosis of CIPA and is the first to propose that congenital loss of permanent teeth may occur in CIPA patients. Furthermore, it highlights the importance of including an oral and maxillofacial surgeon and a pediatric dentist on the multidisciplinary team.

Upregulated miR­20a­5p expression promotes proliferation and invasion of head and neck squamous cell carcinoma cells by targeting of TNFRSF21.

MicroRNAs (miRNAs) play important roles in regulation of proliferation, migration, and invasion of head and neck squamous cell carcinoma (HNSCC). The present study assessed expression, functions and mechanisms of miR­20a­5p in the regulation of HNSCC cell proliferation, migration and invasion. miR­20a­5p expression in HNSCC cell lines and tissues was detected using qRT­PCR, while miR­20a­5p mimics and inhibitor were transfected into HNSCC cells for assessment of the effects using different assays (CCK­8, wound healing and Transwell assays) and expression of miR­20a­5p­targeting genes (using western blot and luciferase reporter assays). The data revealed that miR­20a­5p was upregulated in both HNSCC tissues and metastatic HNSCC cells. Upregulated miR­20a­5p expression in HNSCC cells promoted tumor cell proliferation, migration and invasion capacities, but resulted in downregulation of TNFRSF21 expression and in turn upregulation of C­C motif chemokine receptor 7 (CCR7) in HNSCC cells. Concordantly, knockdown of miR­20a­5p in HNSCC had the opposite results. In conclusion, miR­20a­5p functioned as an oncogene in HNSCC by downregulating TNFRSF21 and subsequently, upregulating CCR7 expression.

Overexpression of hsa-miR-125a-5p enhances proliferation, migration and invasion of head and neck squamous cell carcinoma cell lines by upregulating C-C chemokine receptor type 7.

Head and neck squamous cell carcinoma (HNSCC) is usually diagnosed accompanied by lymph node metastasis. C-C chemokine receptor type 7 (CCR7) is associated with the invasion and metastasis of tumors in HNSCC through various signaling pathways. The role of hsa-miR-125a-5p in HNSCC remains unclear. The present study was performed to investigate the association between hsa-miR-125a-5p and CCR7 in HNSCC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze the expression of hsa-miR-125a-5p in clinical samples. Cell Counting Kit-8, Transwell and wound healing assays were used to detect cell proliferation, invasion, and metastasis, respectively, following overexpression of hsa-miR-125a-5p. Changes in protein expression of CCR7 were observed using western blotting. In the survival analysis, Student's t-tests and log rank tests were performed to analyze the association between the expression of hsa-miR-125a-5p, and HNSCC according to the Cancer Genome Atlas database. The expression of hsa-miR-125a-5p was identified to be significantly lower in cancer tissue compared with the corresponding adjacent normal tissues in clinical samples (P=0.038). The results of western blotting indicated that there was a positive regulatory association between hsa-miR-125a-5p and CCR7. Furthermore, overexpression of hsa-miR-125a-5p significantly enhanced the ability of cell proliferation, migration and invasion in HNSCC, with upregulation of CCR7. The results of survival analysis revealed that patients in the low expression group of hsa-miR-125a-5p tended to have longer survival times compared with the high expression group (P=0.045). Altogether, the data raised the possibility that hsa-miR-125a-5p has a significant role in promoting cancer in HNSCC, which may provide a basis for the treatment of HNSCC in molecular targeted therapy. Further studies are required to ascertain the role of hsa-miR-125a-5p in other HNSCC cell lines and in vivo.

Clinical study of tuberculosis in the head and neck region-11 years' experience and a review of the literature.

Tuberculosis (TB) is an infectious disease and major health concern. Head and neck tuberculosis (HNTB) is relatively rare, but can arise in many regions, including the lymph nodes, larynx, oral cavity and pharynx. We retrospectively reviewed the clinical records of 60 patients diagnosed with HNTB in our department between March 2005 and January 2016. A review and summary of previous HNTB articles published in PubMed since 1885 was also performed. The subjects consisted of 17 males and 43 females, and the average age of patients was 45 ± 14.67 years. The major clinical presentation was a lump or swelling, followed by an oral ulcer and skin fistula. The most common site of tuberculosis was in the cervical lymph node. Three patients also suffered from a malignant tumor in the head and neck region. A total of 980 papers involving 5881 patients were included in our literature review. The included subjects ranged in age from 15 months to 100 years with a male-to-female ratio of 1.5:1. The larynx (38.92%), cervical lymph nodes (38.28%) and oral cavity (9.92%) were the three most common development sites. 465 patients were positive according to a HIV test, and 40 patients had comorbidities with different types of tumors. Head and neck tuberculosis should always be considered during a differential diagnosis for lesions in the head and neck region. Early diagnosis and treatment can greatly enhance the therapeutic effect and patients' quality of life.

Discontinuous Versus In-Continuity Neck Dissection in Squamous Cell Carcinoma of the Tongue and Floor of the Mouth: Comparing the Rates of Locoregional Recurrence.

PURPOSE: To date, consensus has not been reached on which treatment modality, that is, in-continuity neck dissection or discontinuous neck dissection, is more appropriate for managing patients with squamous cell carcinoma (SCC) of the tongue and floor of the mouth. This study aimed to perform a meta-analysis to compare discontinuous neck dissection with in-continuity neck dissection as a treatment modality for SCC of the tongue and floor of the mouth. MATERIALS AND METHODS: The PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched for articles that compared discontinuous neck dissection with in-continuity neck dissection in SCC of the tongue and floor of the mouth until March 1, 2017. The predictor variable was whether discontinuous neck dissection or in-continuity neck dissection was performed in each group. The primary outcome variable was the incidence of locoregional recurrence. Two authors individually extracted the data and assessed the study quality. The meta-analysis was performed using Stata (version 13.0; StataCorp, College Station, TX). RESULTS: We included 8 studies with 796 patients in our meta-analysis. The results showed that in-continuity neck dissection had a statistically significantly lower incidence of locoregional recurrence than discontinuous neck dissection (random-effects model: relative risk, 0.459; 95% confidence interval, 0.240 to 0.877; P = .019). Because significant heterogeneity among studies (I2 = 74.5%, P < .001) was found in the heterogeneity evaluation, a separate analysis was performed. However, the results still showed that in-continuity neck dissection had a statistically significantly lower rate of locoregional recurrence than discontinuous neck dissection in patients with T2 and T3 SCC of the tongue and floor of the mouth (fixed-effects model: relative risk, 0.281; 95% confidence interval, 0.183 to 0.433; P < .001). CONCLUSIONS: Compared with discontinuous neck dissection, in-continuity neck dissection can significantly reduce the rate of locoregional recurrence in patients with SCC of the tongue and floor of the mouth.

MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7.

PURPOSE: miRNAs can play vital role in migration, invasion and proliferation in Squamous cell carcinoma of head and neck (SCCHN). In our study, we attempted to validate the expression and function of miR-1275 in SCCHN, and we also identified the mechanism by which miR-1275 affects migration, invasion and proliferation of SCCHN. METHODS: Real-time polymerase chain reaction (RT-PCR) was employed to evaluate the expression of miR-1275 in both SCCHN tissues and cell lines. The role of miR-1275 in SCCHN cells was verified by cell function experiments upon transfection with miR-1275 mimics and inhibitor. Western blot analysis was employed to test the target gene expression of miR-1275. Survival analysis was made with the information of SCCHN patients expressed miR-1275 from The Cancer Genome Atlas (TCGA) database. RESULTS: miR-1275 expression was up-regulated in SCCHN tissues and advanced metastatic SCCHN cells. Increasing miR-1275 expression in SCCHN could promote cell migration, invasion and proliferation probably by upregulating Insulin-like growth factor 1 receptor (IGF-1R) and C-C chemokine receptor type 7(CCR7) protein levels, whereas inhibition of miR-1275 could lead the opposite effects, although others have already demonstrated that IGF-1R is a direct target of miR-1275. Survival analysis suggested that patients with lower miR-1275 expression may have a better outcome. CONCLUSIONS: Herein we report for the first time that miR-1275 could act as a tumor-promoter in SCCHN possibly by regulating its target gene via novel miRNA mechanisms. MiR-1275 plays an important role in promoting SCCHN progression. The miR-1275 may be a potential therapeutic target for SCCHN treatment in the future.

A comparison of mandible preservation method and mandibulotomy approach in oral and oropharyngeal cancer: A meta-analysis.

OBJECTIVE: This study aims to compare the prognoses outcomes of mandibular preservation method (MPM) and the mandibulotomy approach (MLA) in oral and oropharyngeal cancer (OOPC) patients. METHOD: We searched PubMed, Web of Science, EMBASE, Chinese BioMedical Literature Database (CBM), Cochrane Library, and clinicaltrials.gov up to September 2016 to identify the studies that compared the prognoses of the MPM versus the MLA in OOPC patients. Two authors individually extracted the data and performed quality assessment. The surgical margins, overall survival rate, total and local recurrence rates, fistula formation, and other functional outcomes were evaluated. RESULT: Six studies with 309 patients were included in our analysis. No significant difference was found regarding the surgical margins, overall survival rate, total and local recurrence rates, and speech and tongue movement between the MPM and MLA groups. However, the MPM group showed a significantly lower fistula formation rate than the MLA group after the operation. CONCLUSION: These findings suggest that the MPM may provide a similar clinical outcome to the MLA, but that the MPM has a lower complication rate in the treatment of OOPC patients.

The Role of Sonic Hedgehog Signaling in Osteoclastogenesis and Jaw Bone Destruction.

Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of SHH in bone destruction associated with oral squamous cell carcinomas is still unclear. In this study we analyzed SHH expression and the role played by SHH signaling in gingival carcinoma-induced jawbone destruction. From an analysis of surgically resected lower gingival squamous cell carcinoma mandible samples, we found that SHH was highly expressed in tumor cells that had invaded the bone matrix. On the other hand, the hedgehog receptor Patched and the signaling molecule Gli-2 were highly expressed in the osteoclasts and the progenitor cells. SHH stimulated osteoclast formation and pit formation in the presence of the receptor activator for nuclear factor-κB ligand (RANKL) in CD11b+ mouse bone marrow cells. SHH upregulated phosphorylation of ERK1/2 and p38 MAPK, NFATc1, tartrate-resistant acid phosphatase (TRAP), and Cathepsin K expression in RAW264.7 cells. Our results suggest that tumor-derived SHH stimulated the osteoclast formation and bone resorption in the tumor jawbone microenvironment.

Expression and Role of Sonic Hedgehog in the Process of Fracture Healing with Aging.

Aging is one of the risk factors for delayed fracture healing. Sonic hedgehog (SHH) protein, an inducer of embryonic development, has been demonstrated to be activated in osteoblasts at the dynamic remodeling site of a bone fracture. Herein, we compared and examined the distribution patterns of SHH and the functional effect of SHH signaling on osteogenesis and osteoclastogenesis between young (5-week-old) and aged (60-week-old) mice during fracture healing. We found that SHH was expressed in bone marrow cells from the fractured site of the rib of young mice on day 5, but was barely detectable in the corresponding cells from the rib of aged mice. SHH was also detected in osteoblasts and bone marrow cells at the callus remodeling stage on days 14 and 28 in both young and aged mice. The number of alkaline phosphatase (ALP)-positive osteoblasts was significantly higher in young mice on days 5 and 14, whereas the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was significantly higher in aged mice. SHH stimulated significantly more osteoblast formation in the young compared to old mice. SHH stimulated the osteoclast formation directly in the aged mice and suppressed the formation indirectly through osteoprotegerin expression in the young mice. Results indicate that an aged-related delay of fracture healing may contribute to the unbalanced bone formation and resorption, regulated by hedgehog signaling.

Expression pattern of sonic hedgehog signaling and calcitonin gene-related peptide in the socket healing process after tooth extraction.

Sonic Hedgehog (SHH), a neural development inducer, plays a significant role in the bone healing process. Calcitonin gene-related peptide (CGRP), a neuropeptide marker of sensory nerves, has been demonstrated to affect bone formation. The roles of SHH signaling and CGRP-positive sensory nerves in the alveolar bone formation process have been unknown. Here we examined the expression patterns of SHH signaling and CGRP in mouse socket by immunohistochemistry and immunofluorescence analysis. We found that the expression level of SHH peaked at day 3 and was then decreased at 5 days after tooth extraction. CGRP, PTCH1 and GLI2 were each expressed in a similar pattern with their highest expression levels at day 5 and day 7 after tooth extraction. CGRP and GLI2 were co-expressed in some inflammatory cells and bone forming cells. In some areas, CGRP-positive neurons expressed GLI2. In conclusion, SHH may affect alveolar bone healing by interacting with CGRP-positive sensory neurons and thus regulate the socket's healing process after tooth extraction.