RESUMO
Fibroblast growth factor-23 (FGF23) is a hormone that modulates circulating phosphate (P(i)) levels by controlling P(i) reabsorption from the kidneys. When FGF23 levels are deficient, as in tumoral calcinosis patients, hyperphosphatemia ensues. We show here in a murine model that Fgf23 ablation disrupted morphology and protein expression within the dentoalveolar complex. Ectopic matrix formation in pulp chambers, odontoblast layer disruption, narrowing of periodontal ligament space, and alteration of cementum structure were observed in histological and electron microscopy sections. Because serum P(i) levels are dramatically elevated in Fgf23(-/-), we assayed for apoptosis and expression of members from the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, both of which are sensitive to elevated P(i) in vitro. Unlike X-linked hypophosphatemic (Hyp) and wild-type (WT) specimens, numerous apoptotic osteocytes and osteoblasts were detected in Fgf23(-/-) specimens. Further, in comparison to Hyp and WT samples, decreased bone sialoprotein and elevated dentin matrix protein-1 protein levels were observed in cementum of Fgf23(-/-) mice. Additional dentin-associated proteins, such as dentin sialoprotein and dentin phosphoprotein, exhibited altered localization in both Fgf23(-/-) and Hyp samples. Based on these results, we propose that FGF23 and (P(i)) homeostasis play a significant role in maintenance of the dentoalveolar complex.
Assuntos
Processo Alveolar/patologia , Fatores de Crescimento de Fibroblastos/genética , Hiperfosfatemia/patologia , Animais , Proteínas da Matriz Extracelular/metabolismo , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fator de Crescimento de Fibroblastos 23 , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Hiperfosfatemia/genética , Hiperfosfatemia/metabolismo , Camundongos , Camundongos Knockout , Osteócitos/metabolismo , Fosfatos/metabolismoRESUMO
BACKGROUND: Cementogenesis is sensitive to altered local phosphate levels; thus, we hypothesized a cementum phenotype, likely of decreased formation, would be present in the teeth of X-linked hypophosphatemic (Hyp) mice. Mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex) cause X-linked hypophosphatemia, characterized by rickets, osteomalacia, and hypomineralized dentin formation, a phenotype recapitulated in the Hyp mouse homolog. Here, we report a developmental study of tooth root formation in Hyp mouse molars, focusing on dentin and cementum. METHODS: Light and transmission electron microscopy were used to study molar tissues from wild-type (WT) and Hyp mice. Demineralized and hematoxylin and eosin-stained tissues at developmental stages 23 to 96 days postcoital (dpc) were examined by light microscopy. Immunohistochemistry methods were used to detect bone sialoprotein (BSP) distribution in Hyp and WT mouse molar tissues, and transmission electron microscopy was used to study similar molar tissues in the non-demineralized state. RESULTS: Dentin in Hyp mice exhibited mineralization defects by 33 dpc, as expected, but this defect was partially corrected by 96 dpc. In support of our hypothesis, a cementum phenotype was detected using a combination of immunohistochemistry and transmission electron microscopy, which included thinner BSP-positive staining within the cementum, discontinuous mineralization, and a globular appearance compared to WT controls. CONCLUSION: Mutations in the phosphate-regulating Phex gene of the Hyp mouse resulted in defective cementum development.
Assuntos
Cementogênese/genética , Cemento Dentário/anormalidades , Raquitismo Hipofosfatêmico Familiar/patologia , Doenças Genéticas Ligadas ao Cromossomo X , Animais , Cemento Dentário/patologia , Dentina/anormalidades , Dentina/patologia , Dentinogênese/genética , Feminino , Idade Gestacional , Imuno-Histoquímica , Sialoproteína de Ligação à Integrina , Masculino , Camundongos , Camundongos Mutantes , Microscopia Eletrônica de Transmissão , Dente Molar/anormalidades , Dente Molar/patologia , Mutação/genética , Odontogênese/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fenótipo , Sialoglicoproteínas/análise , Calcificação de Dente/genética , Germe de Dente/anormalidades , Germe de Dente/patologia , Raiz Dentária/anormalidades , Raiz Dentária/patologiaRESUMO
Neuroendocrine gut and pancreatic tumors have provided a diagnostic and therapeutic challenge over the years. Although they are considered slow growing, when disseminated their prognosis is poor. Currently, the various therapeutic options available for patients with inoperable GEP tumors aim either to control symptoms engendered by bioactive mediators, released by tumor cells, or to achieve control of tumor proliferation. The interpretation of the efficacy of the cytotoxic therapy on GEP tumors is hampered by the small size of the studies performed and the inconsistence in tumor type, origin and degree of differentiation. Nevertheless, it is widely recognized that chemotherapy has some role in the management of Neuroendocrine Pancreatic Tumors (NPTs); while in Metastatic Carcinoid Tumors (MCTs) it has only a minimal effect.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , HumanosRESUMO
Two patients with long-standing chronic bronchial suppuration developed antineutrophil cytoplasmic antibody (ANCA) positive Wegener's granulomatosis and microscopic polyarteritis respectively. There is published evidence of an association between previous suppurative respiratory disease and Wegener's granulomatosis. We believe that our cases provide further evidence that chronic lung infection may play an aetiological role in the development of ANCA-positive systemic necrotizing vasculitis in some individuals.