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PubMed2003

Expression and role of Lhx8 in murine tooth development.

We examined the expression and possible functions of Lhx8, a member of the LIM-homeobox gene family, during tooth morphogenesis of the mouse. Lhx8 was expressed in the dental mesenchyme between the bud and early bell stage of the molar tooth germ. Tooth germ explants from embryonic day 12.5 mice treated for 5 to 7 days with antisense-oligodeoxynucleotides (AS-ODN) against Lhx8 showed a marked decrease in the number of mesenchymal cells. The explants treated with AS-ODN for 11 to 14 days were filled with a large number of undifferentiated epithelial cells and a limited number of undifferentiated mesenchymal cells, but did not contain a tooth germ. Treatment of explants with AS-ODN for 7 days suppressed the proliferation of dental mesenchymal cells and induced apoptosis; the latter was confirmed by histochemical and ultrastructural examinations. Moreover, the expression of Lhx6, Msx1, Msx2, Bmp4 and Gsc, which are also known to be involved in tooth morphogenesis, were suppressed after the application of AS-ODN against Lhx8 for 7 days. The present results suggest that Lhx8 plays an important role in the survival of mesenchymal cells of the tooth germ during development.

Animals↗
PubMed2007

Implants in children with ectodermal dysplasia: a case report and literature review.

The replacement of teeth by implants is usually restricted to patients with completed craniofacial growth. Implant insertions in children or adolescents are circumvented due to several unfavorable potential effects including trauma to tooth germs, tooth eruption disorders and multidimensional restrictions of skeletal craniofacial growth. Moreover, the functional and esthetic results of the oral rehabilitation are only temporary acceptable. However, to a small number of pediatric patients suffering congenitally from severe hypodontia caused by syndromes such as ectodermal dysplasia, conventional prosthodontic rehabilitations are insufficient. We report the case of a boy with ectodermal dysplasia who exhibited a severe hypodontia and who was treated with implants inserted into the anterior mandible at the age of 8 years. The implants were functionally loaded and resulted in a high patient satisfaction. We recommend the early insertion of dental implants in children with severe hypodontia. Reviewing the current literature, several aspects of syndromic hypodontia, patient selection and implant planning are discussed.

Anodontia↗
PubMed2006

Establishment of immortalized dental follicle cells for generating periodontal ligament in vivo.

The dental follicle is a mesenchymal tissue that surrounds the developing tooth germ. During tooth root formation, periodontal components, viz., cementum, periodontal ligament (PDL), and alveolar bone, are created by dental follicle progenitors. Here, we report the presence of PDL progenitors in mouse dental follicle (MDF) cells. MDF cells were obtained from mouse incisor tooth germs and immortalized by the expression of a mutant human papilloma virus type 16 E6 gene lacking the PDZ-domain-binding motif. MDF cells expressing the mutant E6 gene (MDF( E6-EGFP ) cells) had an extended life span, beyond 150 population doublings (PD). In contrast, normal MDF cells failed to proliferate beyond 10 PD. MDF( E6-EGFP ) cells expressed tendon/ligament phenotype-related genes such as Scleraxis (Scx), growth and differentiation factor-5, EphA4, Six-1, and type I collagen. In addition, the expression of periostin was observed. To elucidate the differentiation capacity of MDF( E6-EGFP ) cells in vivo, the cells were transplanted into severe combined immunodeficiency mice. At 4 weeks, MDF( E6-EGFP ) cell transplants had the capacity to generate a PDL-like tissue that expressed periostin, Scx, and type XII collagen and the fibrillar assembly of type I collagen. Our findings suggest that MDF( E6-EGFP ) cells can act as PDL progenitors, and that these cells may be a useful research tool for studying PDL formation and for developing regeneration therapies.

Alkaline Phosphatase↗
PubMed2006

Expression of bone morphogenetic proteins and their associated molecules in ameloblastomas and adenomatoid odontogenic tumors.

OBJECTIVE: To further clarify the roles of regulators of embryonic development, bone morphogenetic protein (BMPs) and their associated molecules, in oncogenesis and cytodifferentiation of odontogenic tumors, the expression of these regulator molecules were analyzed in epithelial odontogenic tumors as well as in tooth germs. MATERIALS AND METHODS: Tooth germs, ameloblastomas, adenomatoid odontogenic tumors, and malignant ameloblastomas were examined by RT-PCR and immunohistochemistry for detection of BMP-2, -4, -7, BMP receptors I and II (BMPR-I, BMPR-II), core-binding factor alpha1 (CBFA1), and osterix. RESULTS: mRNA expression of BMPs, BMPRs, CBFA1, and osterix was detected in all odontogenic tissues. Immunohistochemical reactivity for BMPs, BMPRs, and CBFA1 was detected in both epithelial and mesenchymal cells of tooth germs and epithelial odontogenic tumors. BMPs and BMPRs were evidently expressed in odontogenic epithelial cells in tooth germs and epithelial odontogenic tumors. Acanthomatous ameloblastomas showed increased BMP-7 reactivity in keratinizing cells. Nuclear CBFA1 expression was detected scatteredly in odontogenic epithelial cells in normal and neoplastic odontogenic tissues, as well as in some mesenchymal cells in tooth germs and in some stromal cells in epithelial odontogenic tumors. Ameloblastic carcinomas showed low reactivity for BMPs, BMPRs, and CBFA1. CONCLUSION: BMPs and their associated molecules might play a role in cytodifferentiation of normal and neoplastic odontogenic epithelium via epithelial-mesenchymal interactions.

Ameloblastoma↗
PubMed2001

Immunohistochemical analysis of apoptosis-related factors (Fas, Fas ligand, caspase-3 and single-stranded DNA) in ameloblastomas.

BACKGROUND: To clarify the possible role of apoptotic cell death in oncogenesis and cytodifferentiation of odontogenic epithelium, apoptosis-related factors--Fas, Fas ligand (FasL), caspase-3 and single-stranded DNA (ssDNA)--were analyzed in ameloblastomas as well as in tooth germs. METHODS: Specimens of 5 tooth germs, 29 benign ameloblastomas and 5 malignant ameloblastomas were examined by immunohistochemistry using anti-Fas, FasL, caspase-3 and ssDNA polyclonal antibodies. RESULTS: Immunoreactivity for Fas and FasL was detected in normal and neoplastic odontogenic epithelial cells. Fas expression in ameloblastomas was slightly lower than that in tooth germs, whereas FasL expression was similar in tooth germs and ameloblastomas. Malignant ameloblastomas showed downregulation of Fas expression and upregulation of FasL expression, as compared with benign ameloblastomas, indicating escape from cell death attack by immune cells. Immunoreactivity for caspase-3 was detected chiefly in cells neighboring the basement membrane in tooth germs and ameloblastomas. Expression of caspase-3 and Fas tended to be low in basal cell ameloblastomas and high in desmoplastic ameloblastomas, as compared with other variants of ameloblastomas. Caspase-3 expression was more intense in malignant ameloblastomas than in tooth germs and benign ameloblastomas. Apoptotic bodies reactive with anti-ssDNA antibody were detected in normal and neoplastic odontogenic epithelial cells detached from the basement membrane. Keratinizing cells in acanthomatous ameloblastomas and granular cells in granular cell ameloblastomas showed increased numbers of apoptotic bodies and increased expression of Fas and caspase-3, as compared with other neoplastic cells. Apoptotic reactions in malignant ameloblastomas were less frequent than in benign ameloblastomas, indicating abnormal regulation of cell turnover in odontogenic epithelial cells. CONCLUSION: These apoptosis-related factors were detected in various patterns in normal and neoplastic odontogenic epithelium, suggesting that these factors might be associated with oncogenesis and cytodifferentiation of epithelial odontogenic tumors.

Ameloblastoma↗
PubMed2005

Immunohistochemical detection of beta-catenin and adenomatous polyposis coli in ameloblastomas.

BACKGROUND: To clarify the roles of the Wnt signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, expression of beta-catenin and adenomatous polyposis coli (APC) was analyzed in ameloblastomas as well as in tooth germs. METHODS: Tissue specimens of 10 tooth germs, 40 benign ameloblastomas, and five malignant ameloblastomas were examined immunohistochemically with the use of antibodies against beta-catenin and APC. RESULTS: Immunohistochemical reactivity for beta-catenin was detected in the cell membrane and cytoplasm of most odontogenic epithelial cells in tooth germs and ameloblastomas. Nuclear beta-catenin expression was recognized in nine of 40 ameloblastomas and two of five malignant ameloblastomas, but not in tooth germs. APC was evidently expressed in odontogenic epithelial cells neighboring the basement membrane in tooth germs and ameloblastomas, and the reactivity was significantly lower in benign and malignant ameloblastomas than in tooth germs. Follicular ameloblastomas and acanthomatous ameloblastomas tended to show high nuclear beta-catenin expression and low APC reactivity, as compared with other ameloblastoma variants. CONCLUSION: Expression of beta-catenin and APC in tooth germs and ameloblastomas suggests that aberration of the Wnt signaling pathway might play a role in oncogenesis and cytodifferentiation of odontogenic epithelium via deregulation of cell proliferation.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Immunohistochemical detection of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in ameloblastomas.

BACKGROUND: To evaluate the roles of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression, expression of MMP-1, -2 and -9 and TIMP-1 and -2 was analyzed in ameloblastomas as well as tooth germs. METHODS: Frozen tissue sections of seven tooth germs and 22 ameloblastomas were immunohistochemically examined using anti-MMP-1, -2 and -9 and anti-TIMP-1 and -2 antibodies. RESULTS: MMP-1, -2 and -9 and TIMP-1 and -2 were expressed strongly in mesenchymal components of tooth germs, and stromal cells of ameloblastomas. Immunoreactivity for MMP-9 in stromal cells of ameloblastomas was significantly stronger than in mesenchymal cells of dental follicles and dental papillae. Dental laminae showed weak MMP-2 expression in six tooth germs, MMP-9 expression in two tooth germs and TIMP-1 expression in six tooth germs. Some tumor cells showed weak MMP-2 expression in 19 ameloblastomas, MMP-9 expression in four ameloblastomas and TIMP-1 expression in all cases. TIMP-2 reactivity was prominently found in basement membrane zones of dental laminae in tooth germs, and tumor cell islands or nests in ameloblastomas. CONCLUSION: Expression of MMPs and TIMPs was considered to be associated with interactions between epithelial cells and mesenchymal components in normal and neoplastic odontogenic tissues; these molecules might play a role in regulation of tumor progression in ameloblastomas as well as regulation of developmental processes in tooth germs.

Adolescent↗
PubMed2006

Immunohistochemical detection of platelet-derived endothelial cell growth factor/thymidine phosphorylase and angiopoietins in ameloblastic tumors.

BACKGROUND: To evaluate the roles of angiogenic factors in the development and progression of odontogenic tumors, expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) and of angiopoietins in ameloblastic tumors as well as in tooth germs. METHODS: Tissue specimens of 11 tooth germs, 44 ameloblastomas, and five malignant ameloblastic tumors were examined immunohistochemically with the use of antibodies against PD-ECGF/TP and angiopoietin-1 and -2. RESULTS: Immunohistochemical reactivity for PD-ECGF/TP was detected in mesenchymal cells in tooth germs and stromal cells in ameloblastic tumors, and the level of immunoreactivity for PD-ECGF/TP was significantly higher in ameloblastomas than in tooth germs. Granular cell ameloblastomas showed PD-ECGF/TP reactivity in granular neoplastic cells as well as in stromal cells. Immunoreactivity for angiopoietin-1 and -2 was detected predominantly in odontogenic epithelial cells near the basement membrane in tooth germs and in benign and malignant ameloblastic tumors. Malignant ameloblastic tumors had decreased angiopoietin-1 reactivity and ameloblastic carcinomas had increased angiopoietin-2 reactivity as compared with the respective levels in tooth germs and ameloblastomas. Immunohistochemical reactivity for angiopoietin-2 was slightly higher in follicular ameloblastomas than in plexiform ameloblastomas. CONCLUSION: Expression of PD-ECGF/TP and angiopoietin-1 and -2 in tooth germs and ameloblastic tumors suggests that these angiogenic factors participate in tooth development and odontogenic tumor progression by regulating angiogenesis. Altered expression of PD-ECGF/TP and angiopoietins in ameloblastic tumors may be involved in oncogenesis, malignant potential, and tumor cell differentiation.

Ameloblastoma↗
PubMed2002

Immunohistochemical analysis of inducible nitric oxide synthase (iNOS) and heat shock proteins (HSPs) in ameloblastomas.

BACKGROUND: To clarify the possible role of nitric oxide (NO) and stress proteins in oncogenesis and cytodifferentiation of odontogenic epithelium. Inducible NO synthase (iNOS) and heat shock proteins (HSPs) were analyzed in ameloblastomas as well as in tooth germs. METHODS: Specimens of seven tooth germs, 36 benign ameloblastomas and five malignant ameloblastomas were examined by immunohistochemistry using antibodies against iNOS and 27-, 60- and 70-kDa HSPs (HSP27, HSP60 and HSP70). RESULTS: Immunoreactivity for iNOS was detected in normal and neoplastic odontogenic epithelial cells and was higher in malignant ameloblastomas than in tooth germs and benign ameloblastomas. HSP27 was expressed constitutively in all odontogenic epithelial cells in tooth germs and benign and malignant ameloblastomas. Expression of HSP60 and HSP70 was detected in normal and neoplastic odontogenic epithelial cells and was prominent in cells neighboring the basement membrane. HSP60 reactivity showed no apparent difference between normal and neoplastic odontogenic epithelium, whereas HSP70 expression was slightly higher in benign and malignant ameloblastomas than in tooth germs. CONCLUSIONS: Activation of iNOS might be associated with malignant potential of epithelial odontogenic tumors. Elevated expression of HSP70 is considered to be involved in neoplastic transformation of odontogenic epithelial cells.

Ameloblastoma↗
PubMed2006

Immunohistochemical detection of MT1-MMP, RECK, and EMMPRIN in ameloblastic tumors.

BACKGROUND: To evaluate the roles of matrix-degrading proteinase regulators in progression of odontogenic tumors, expression of membrane-bound matrix metalloproteinase (MMP) MT1-MMP, MMP inhibitor RECK and MMP inducer EMMPRIN was analyzed in ameloblastic tumors as well as in tooth germs. METHODS: Tissue specimens of 11 tooth germs, 40 ameloblastomas, and five malignant ameloblastic tumors were examined immunohistochemically with the use of antibodies against MT1-MMP, RECK, and EMMPRIN. RESULTS: Immunohistochemical reactivity for MT1-MMP, RECK and EMMPRIN was detected predominantly in odontogenic epithelial cells near the basement membrane in tooth germs and benign and malignant ameloblastic tumors. The level of immunoreactivity for MT1-MMP was slightly higher in benign and malignant ameloblastic tumors than in tooth germs. RECK expression was lower in ameloblastomas than in tooth germs. Follicular ameloblastomas showed significantly lower expression of RECK than plexiform ameloblastomas, and immunoreactivity for RECK in acanthomatous ameloblastomas was slightly lower than that in other cellular variants. CONCLUSION: Expression of MT1-MMP, RECK and EMMPRIN in tooth germs and ameloblastic tumors suggests that these normal and neoplastic epithelial components control MMP-dependent extracellular matrix (ECM) degradation during tooth development and tumor progression via epithelial-mesenchymal interactions.

Ameloblastoma↗
PubMed2002

Immunohistochemical detection of hepatocyte growth factor, transforming growth factor-beta and their receptors in epithelial odontogenic tumors.

BACKGROUND: Tumors derived from odontogenic epithelium exhibit considerable variation and are classified into several benign and malignant entities. To clarify the role of growth factors in oncogenesis, cytodifferentiation and progression of epithelial odontogenic tumors, expression of hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-beta) and their receptors were analyzed in these tumors as well as in tooth germs. METHODS: Specimens of five tooth germs, 34 ameloblastomas, three calcifying epithelial odontogenic tumors (CEOTs), two clear cell odontogenic tumors (CCOTs), five adenomatoid odontogenic tumors (AOTs), six calcifying odontogenic cysts (COCs) and six malignant ameloblastomas were examined immunohistochemically with the use of antibodies against HGF, TGF-beta and their receptors. RESULTS: In tooth germs and epithelial odontogenic tumors, immunoreactivity for HGF and TGF-beta was detected in both epithelial and mesenchymal cells, while expression of their receptors was found only in epithelial cells. In tooth germs and main types of ameloblastomas, HGF and TGF-beta reactivity was marked in epithelial cells near the basement membrane, and their receptors were diffusely positive in most epithelial cells. In subtypes of ameloblastomas, reduced expression of HGF, c-Met and TGF-beta and increased reactivity for TGF-beta receptors were detected in keratinizing cells in acanthomatous ameloblastomas, and granular cells in granular cell ameloblastomas demonstrated little or no expression of HGF, TGF-beta or their receptors. As compared with main types of ameloblastomas, basal cell ameloblastomas showed high HGF reactivity, and desmoplastic ameloblastomas exhibited elevated reactivity for TGF-beta and its receptors. Neoplastic cells in CEOTs, AOTs and COCs showed reactivity for HGF, TGF-beta and their receptors. Elevated HGF and TGF-beta reactivity was found in pseudoglandular cells in AOTs, and high expression of their receptors was noted in ghost cells in COCs. Metastasizing ameloblastomas showed similar expression patterns of HGF, TGF-beta and their receptors to those of benign ameloblastomas, while CCOTs and ameloblastic carcinomas had increased HGF expression and low reactivity for TGF-beta and its receptors as compared with benign ameloblastomas. CONCLUSIONS: Immunohistochemical localization of HGF, TGF-beta and their receptors in tooth germs and epithelial odontogenic tumors supports the hypothesis that HGF and TGF-beta act on epithelial cells via paracrine and autocrine mechanisms. Altered expression of the agents in these epithelial odontogenic tumors, especially subtypes of ameloblastomas, AOTs and COCs, suggests that HGF and TGF-beta signaling might affect differentiation of neoplastic odontogenic epithelial cells. Activated HGF/c-Met pathway and reduced TGF-beta signaling in CCOTs and ameloblastic carcinomas may be associated with the malignant potential of these epithelial odontogenic tumors.

Cell Transformation, Neoplastic↗
PubMed2004

Expression of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) in ameloblastomas.

BACKGROUND: To clarify the roles of osteoclast regulatory factors in progression of odontogenic tumors, expression of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL), and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) were analyzed in ameloblastomas as well as tooth germs. METHODS: Tissue specimens of nine tooth germs and 36 benign and one malignant ameloblastomas were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry for the expression of PTHrP, ODF/RANKL, and OCIF/OPG. RESULTS: Expression of PTHrP, ODF/RANKL, and OCIF/OPG mRNA was detected in all tooth germ and ameloblastoma samples. Immunohistochemical reactivity for PTHrP was recognized in both normal and neoplastic odontogenic epithelial cells. In ameloblastomas, PTHrP reactivity in peripheral columnar or cuboidal cells was stronger than that in central polyhedral cells, and keratinizing cells showed increased PTHrP reactivity. ODF/RANKL and OCIF/OPG were expressed predominantly in mesenchymal cells rather than in odontogenic epithelial cells in both tooth germs and ameloblastomas. Epithelial ODF/RANKL and OCIF/OPG expression was slightly lower in ameloblastomas than in tooth germs. Tumor cells in plexiform ameloblastomas showed slightly higher reactivity for PTHrP and ODF/RANKL than tumor cells in follicular ameloblastomas. CONCLUSION: Expression of PTHrP, ODF/RANKL and OCIF/OPG in tooth germs and ameloblastomas suggests that these factors might locally regulate bone metabolism and dynamics in tooth development as well as in progression of ameloblastomas. These factors might also be involved in tumor cell differentiation and/or tumor tissue structuring in ameloblastomas.

Ameloblastoma↗
PubMed2005

Expression of tumor necrosis factor alpha, TNF-related apoptosis-inducing ligand, and their associated molecules in ameloblastomas.

BACKGROUND: To clarify the roles of the apoptosis signaling pathway mediated by death receptors in oncogenesis and cytodifferentiation of odontogenic tumors, expression of tumor necrosis factor alpha (TNFalpha), TNF-related apoptosis-inducing ligand (TRAIL), and their associated molecules was analyzed in ameloblastomas as well as in tooth germs. METHODS: Tissue specimens of 10 tooth germs, 40 benign ameloblastomas, and five malignant ameloblastomas were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry to determine the expression of TNFalpha, TNF receptor I (TNFRI), TRAIL, TRAIL receptor 1 (TRAIL-R1), TRAIL-R2, caspase-8, and nuclear factor-kappaB (NF-kappaB). RESULTS: Expression of TNFalpha, TNFRI, TRAIL, TRAIL-R1, TRAIL-R2, and NF-kappaB mRNA was detected in most samples of normal and neoplastic odontogenic tissues. Expression of caspase-8 mRNA was identified in six of 33 ameloblastomas, but not in 10 tooth germs or one malignant ameloblastoma. Immunohistochemical reactivity for TNFalpha, TRAIL, their receptors, and NF-kappaB was detected in both normal and neoplastic odontogenic tissues. Epithelial expression of TNFalpha was focal in about 50% of tooth germs and ameloblastomas, and TNFalpha expression in neoplastic cells was significantly higher in follicular ameloblastomas than in plexiform ameloblastomas. TRAIL reactivity was evident in epithelial cells neighboring the basement membrane. Receptors for TNFalpha and TRAIL were diffusely expressed in both normal and neoplastic odontogenic epithelium. Expression of caspase-8 was found in some neoplastic cells in three of 37 ameloblastomas, but not in 10 tooth germs or five malignant ameloblastomas. Nuclear NF-kappaB expression was much lower than cytoplasmic expression in both normal and neoplastic odontogenic epithelium. CONCLUSION: Expression of TNFalpha, TRAIL, and their receptors in tooth germs and ameloblastomas suggests that these death factors might be involved in cytodifferentiation of odontogenic epithelium and tissue structuring of ameloblastomas. Expression of caspase-8 and NF-kappaB suggests that signaling of TNFalpha and TRAIL minimally affects the biological properties of odontogenic epithelial components.

Ameloblastoma↗
PubMed2002

Disturbed tooth development in parathyroid hormone-related protein (PTHrP)-gene knockout mice.

Parathyroid hormone-related protein (PTHrP) is involved in epithelial-mesenchymal cell interactions during development of various tissues and organs. Tooth germ development is a classical model for this interaction. In tooth germs, PTHrP is expressed in the enamel organ (epithelial component), whereas its major receptor, the type I PTH/PTHrP receptor is expressed in cells of the alveolar bone and dental follicle (mesenchymal components). To clarify the role of PTHrP during fetal tooth germ development, PTHrP gene-knockout mice were used for histochemical and ultrastructural analysis. In wild-type mice, osteoclastic cells were aligned predominantly in the inner aspects of the alveolar bone surrounding the developing tooth germs throughout the late embryonic (after embryonic, 17.5 days) and neonatal animals examined. In contrast, osteoblasts were predominant in corresponding areas of fetal homozygous PTHrP-gene knockout mice with only occasional osteoclasts. In such areas, cell-free surfaces showing cement line-like tartrate-resistant acid phosphatase (TRAP) reactions were frequently observed. In neonatal homozygous mice, bone spicules were often shown to penetrate and/or compress the enamel organ and caused partial destruction of the tooth germs. Osteoclasts were few in number in the inner aspects of the alveolar bone, and had poorly developed ruffled border. No morphological abnormality was noted in cells of the tooth germs proper. On bone surfaces away from developing tooth germs, functional osteoclasts with structural features similar to those in wild-type mice were observed in homozygous mice. These observations suggest that PTHrP is required to maintain an appropriate spatiotemporal arrangement of bone cells and osteoclast function, which are necessary for the normal development of tooth germ and alveolar bone encasing the tooth germ. The observation also demonstrates that PTHrP deficiency affects the structure and function of osteoclasts exclusively those located in the vicinity of the growing tooth germ.

Acid Phosphatase↗
PubMed2004

p53 gene status and expression of p53, MDM2, and p14 proteins in ameloblastomas.

BACKGROUND: To clarify the roles of the p53-MDM2-p14(ARF) cell cycle regulation system in oncogenesis and cytodifferentiation of odontogenic tumors, p53 gene status and expression of p53, MDM2, and p14(ARF) proteins was analyzed in ameloblastomas as well as tooth germs. METHODS: Paraffin sections of 16 tooth germs and 46 benign and 5 malignant ameloblastomas were examined immunohistochemically for the expression of p53, MDM2, and p14(ARF) proteins. Frozen tissue samples of 10 benign ameloblastomas and 1 malignant (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect p53 gene alteration. RESULTS: Immunohistochemical reactivity for p53 was detected in 2 of 13 tooth germs, 13 of 29 ameloblastomas, and 5 of 5 malignant ameloblastomas, and the expression ratio of p53 in tooth germs was significantly lower than those in benign and malignant ameloblastomas. Direct DNA sequencing showed no alteration of p53 gene exons 5-8 in any sample of 10 benign ameloblastomas and 1 metastasizing ameloblastoma. Expression of MDM2 and p14(ARF) was detected in all samples of normal and neoplastic odontogenic epithelium, and the expression ratios in tooth germs tended to be lower than those in benign and malignant ameloblastomas. In ameloblastomas, expression of p53, MDM2, and p14(ARF) was significantly higher in plexiform cases than in follicular cases. Markedly decreased reactivity for p53, MDM2, and p14(ARF) was detected in keratinizing and granular cells in ameloblastoma subtypes. Basal cell ameloblastoma showed slightly higher reactivity for p53, MDM2, and p14(ARF) as compared with other subtypes. CONCLUSION: Elevated expression of p53, MDM2, and p14(ARF) in benign and malignant ameloblastomas suggests that alteration of the p53-MDM2-p14(ARF) cascade is involved in oncogenesis and/of malignant transformation of odontogenic epithelium. p53 gene status implied that p53 mutation might play a minor role in neoplastic changes of odontogenic epithelium. Immunoreactivity for p53, MDM2, and p14(ARF) in ameloblastoma variants suggests that these factors might be associated with tissue structuring and cytodifferentiation of ameloblastomas.

Ameloblastoma↗
PubMed2004

Expression of Sonic hedgehog (SHH) signaling molecules in ameloblastomas.

BACKGROUND: To clarify the roles of Sonic hedgehog (SHH) signal transduction in oncogenesis and cytodifferentiation of odontogenic tumors, expression of SHH, Patched (PTC), Smoothened (SMO), and GLI1 was analyzed in ameloblastomas as well as in tooth germs. METHODS: Tissue specimens of 9 tooth germs, 36 benign ameloblastomas, and 1 malignant ameloblastoma were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry for the expression of SHH, PTC, SMO, and GLI1. RESULTS: Expression of SHH, PTC, SMO, and GLI1 mRNA was detected in all tooth germ and ameloblastoma samples. Immunohistochemical reactivity for SHH, PTC, SMO, and GLI1 was detected in both normal and neoplastic odontogenic tissues. Expression of SHH, PTC, and GLI1 was more evident in epithelial cells than in mesenchymal cells, whereas SMO reactivity was marked in both epithelial and mesenchymal components in tooth germs and ameloblastomas. In ameloblastomas, these SHH signaling molecules were expressed more intensely in peripheral columnar or cuboidal cells than in central polyhedral cells; keratinizing cells and granular cells showed no or little reactivity. CONCLUSION: Expression of SHH, PTC, SMO, and GLI1 in tooth germs and ameloblastomas suggests that these SHH signaling molecules might play a role in epithelial-mesenchymal interactions and cell proliferation in tooth development as well as in growth of these epithelial odontogenic tumors.

Ameloblastoma↗
PubMed2006

Immunohistochemical detection of retinoblastoma protein and E2 promoter-binding factor-1 in ameloblastomas.

BACKGROUND: To clarify the roles of cell cycle regulation in oncogenesis and cytodifferentiation of odontogenic tumors, expression of retinoblastoma protein (RB) and E2 promoter-binding factor-1 (E2F-1) was analyzed in ameloblastomas as well as in tooth germs. METHODS: Tissue specimens of 10 tooth germs, 40 benign ameloblastomas, and five malignant ameloblastomas were examined immunohistochemically with the use of antibodies against RB, E2F-1, and phosphorylated RB. Ki-67 antigen immunostaining was made as a marker of cell proliferation. RESULTS: Immunohistochemical reactivity for RB, E2F-1, phosphorylated RB, and Ki-67 was detected in the nuclei of odontogenic epithelial cells near the basement membrane in tooth germs and benign and malignant ameloblastomas. The number of cells positive for phosphorylated RB was nearly equal to or slightly less than the number of cells positive for RB or E2F-1. The number of Ki-67-positive cells was slightly more than the numbers of cell positive for RB, E2F-1, or phosphorylated RB. The levels of immunoreactivity for RB, E2F-1, phosphorylated RB, and Ki-67 were slightly higher in benign and malignant ameloblastomas than in tooth germs. Plexiform ameloblastomas showed significantly higher expression of RB than follicular ameloblastomas. Ki-67 immunoreactivity was significantly higher in ameloblastic carcinomas than in metastasizing ameloblastomas. CONCLUSION: Similar immunoreactivity for RB, E2F-1, phosphorylated RB, and Ki-67 in tooth germs and ameloblastomas indicated cellular expression of phosphorylated RB and active-free E2F-1 in both normal and neoplastic odontogenic tissues. Expression of RB, E2F-1, and phosphorylated RB was considered to be involved in cell proliferation and differentiation of odontogenic epithelium via control of the cell cycle.

Ameloblastoma↗
PubMed1998

Expression of E- and P-cadherin during tooth morphogenesis and cytodifferentiation of ameloblasts.

Cell-cell adhesion is fundamental in morphogenesis and is known to be mediated by several groups of cell adhesion molecules. Cadherins are a group of such molecules involved in the Ca2+-dependent cell-cell adhesion mechanism and are found in most kinds of tissue. In this study using indirect immunofluorescence microscopy, we analyzed the distribution of two kinds of cadherins, E- and P-cadherin, in developing tooth germs. In the molar tooth germs at the early bud stage, marginal cells of the epithelial tooth bud expressed both E- and P-cadherin, whereas central cells expressed only E-cadherin. At the cap stage, in addition to the cells of the inner and outer enamel epithelium, which outline the enamal organ, cells of the enamel knot, which is thought to control tooth morphogenesis, strongly expressed P-cadherin. The expression of P-cadherin was prominent in the inner enamel epithelium during the early to mid bell stage, and was also evident in the non-dividing cell masses at future cusp tips, which are the so-called secondary enamel knots. In the tooth germ at the late bell stage when the cells of the inner enamel epithelium began to polarize to differentiate into ameloblasts, the polarizing ameloblasts lost P-cadherin and strongly expressed E-cadherin. However, E-cadherin was also lost from polarized ameloblasts at later stages. The stratum intermedium and the stellate reticulum were E-cadherin positive from the bell stage onward even at the stages when the ameloblasts became E-cadherin negative again. These results suggest that the differential expression of E- and P-cadherin during morphogenetic stages plays a role in the regulation of tooth morphogenesis, whereas alteration of E-cadherin expression during later stages of tooth development is related to differentiation and function of the ameloblasts and other cells supporting amelogenesis.

Ameloblasts↗