RESUMO
BACKGROUND: While pharmacological activation of the Hedgehog (HH) signaling pathway may have therapeutic benefits for developmental and adult diseases, its teratogenic potential is of concern. The membrane molecule Smoothened (SMO) transduces HH signaling and can be acutely modulated by antagonists and agonists. The objective of the current experiments was to determine how maternal treatment with the Smo agonist, SAG, affects the developing limb. METHODS: Pregnant C57BL/6J mice received a single injection of SAG (15, 17, or 20 mg/kg, i.p.) or its vehicle on gestational day (GD) 9.25, the time of limb bud induction. Embryos were examined on GD 15 for gross dysmorphology and skeletal staining was performed to visualize the number and type of digits on the fore- and hindlimbs. Additionally, in situ hybridization was performed 4 hr after GD 9.25 SAG administration to determine SAG's effects on Gli1 and Gli2 mRNA expression. RESULTS: The most prevalent effect of SAG was the dose-dependent induction of pre-axial polydactyly; defects ranged from a broad thumb to the duplication of two finger-like digits on the preaxial side of the thumb. The highest SAG dose was effective in ca. 80% of the embryos and increased Gli1 and Gli2 mRNA expression in the limb bud, with Gli1 mRNA being the most upregulated. CONCLUSION: Preaxial polydactyly can be caused in the developing embryo by acute maternal administration of a Smo agonist that activates HH signaling. These results are consistent with the preaxial polydactyly induced in developmental disorders associated with mutations in HH signaling genes.Birth Defects Research 109:49-54, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Cicloexilaminas/efeitos adversos , Cicloexilaminas/metabolismo , Polidactilia/fisiopatologia , Tiofenos/efeitos adversos , Tiofenos/metabolismo , Animais , Extremidades , Feminino , Deformidades da Mão/genética , Deformidades da Mão/metabolismo , Proteínas Hedgehog/genética , Botões de Extremidades/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Polidactilia/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais/genética , Receptor Smoothened/agonistas , Receptor Smoothened/metabolismo , Polegar/anormalidades , Polegar/fisiopatologia , Fatores de Transcrição/genética , Proteína GLI1 em Dedos de Zinco/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/efeitos dos fármacos , Proteína Gli2 com Dedos de Zinco/genéticaAssuntos
Contratura de Dupuytren/genética , Deformidades da Mão/genética , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , Contratura de Dupuytren/metabolismo , Contratura de Dupuytren/patologia , Estudo de Associação Genômica Ampla , Deformidades da Mão/metabolismo , Deformidades da Mão/patologia , Humanos , Proteínas Wnt/metabolismoRESUMO
The aim of this study was to demonstrate metabolic changes in the small joints of the hand due to rheumatoid arthritis by means of 31-phosphorus spectroscopy. Suitable measurements were developed and 11 normals and 12 patients were then examined during the course of treatment. Relative concentration of low energy phosphorus metabolites was increased in arthritic joints. The phospholipid quotient (phosphomonoester/phosphodiester) and the relationship of inorganic phosphate and beta-nucleoside triphosphate were significant factors during the course of individual treatments.
Assuntos
Artrite Reumatoide/metabolismo , Deformidades da Mão/metabolismo , Espectroscopia de Ressonância Magnética , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Diclofenaco/uso terapêutico , Feminino , Mãos , Deformidades da Mão/tratamento farmacológico , Humanos , Articulações/metabolismo , Espectroscopia de Ressonância Magnética/instrumentação , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fósforo/metabolismo , Fatores de TempoRESUMO
We report on two brothers with renal hypophosphatemia, intracerebral calcifications, minor facial anomalies, and short distal phalanges. The children presented with recurrent dental abscesses; one had premature closure of the anterior fontanelle. Biochemical findings included hypophosphatemia and elevated serum alkaline phosphatase with normocalcemia. Blood levels of parathyroid hormone, 1,25(OH)2 and 25(OH) vitamin D levels were normal; TRP (the fractional tubular reabsorption of PO4) and TmP/GFR (the tubular maximum rate of PO4 reabsorption in relation to GFR) were low. Both parents had a normal serum phosphate and brain CT scan without evidence of calcifications. This apparently new syndrome of renal hypophosphatemia associated with intracerebral calcifications appears to be inherited as either an autosomal recessive or an X-linked trait.
